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| Skeletal dysplasia v1.147 | MYF5 |
Zornitza Stark changed review comment from: MYF5 variants are associated with skeletal malformations, including congenital scoliosis and external ophthalmoplegia with rib and vertebral anomalies (EORVA), 5 families reported. Sources: Literature; to: MYF5 variants are associated with skeletal malformations, including congenital scoliosis and external ophthalmoplegia with rib and vertebral anomalies (EORVA), 5 families reported and a mouse model. Sources: Literature |
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| Skeletal dysplasia v1.146 | MYF5 |
Zornitza Stark gene: MYF5 was added gene: MYF5 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MYF5 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYF5 were set to 38927634; 35186005; 32815649; 29887215 Phenotypes for gene: MYF5 were set to Ophthalmoplegia, external, with rib and vertebral anomalies, MONDO:0032565 Review for gene: MYF5 was set to GREEN Added comment: MYF5 variants are associated with skeletal malformations, including congenital scoliosis and external ophthalmoplegia with rib and vertebral anomalies (EORVA), 5 families reported. Sources: Literature |
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| Skeletal dysplasia v1.144 | LARP7 |
Zornitza Stark gene: LARP7 was added gene: LARP7 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: LARP7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LARP7 were set to 40129845; 37529055; 26607181; 26374271 Phenotypes for gene: LARP7 were set to microcephalic primordial dwarfism, Alazami type, MONDO:0014031 Review for gene: LARP7 was set to GREEN Added comment: Four individuals from different families reported with biallelic LARP7 variants associated with Alazami syndrome, a microcephalic primordial dwarfism disorder characterised by severe growth failure, profound intellectual disability and distinctive facial dysmorphism; functional studies demonstrate reduced LARP7 protein expression. Sources: Literature |
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| Skeletal dysplasia v1.142 | INTS13 |
Zornitza Stark changed review comment from: PMID 36229431 reports 4 individuals from 2 families with autosomal recessive oral‑facial‑digital syndrome type 2 (OFD2) caused by homozygous loss‑of‑function INTS13 variants; affected individuals present with cleft lip, craniofacial dysmorphism, digital anomalies and short stature. Sources: Literature; to: PMID 36229431 reports 4 individuals from 2 families with autosomal recessive oral‑facial‑digital syndrome type 2 (OFD2) caused by homozygous loss‑of‑function INTS13 variants; affected individuals present with cleft lip, craniofacial dysmorphism, digital anomalies and short stature. INTS13 is a subunit of the Integrator complex, which associates with RNA Polymerase II and cleaves nascent RNA to modulate gene expression. Variants segregated with disease. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Knockdown in Xenopus embryos leads to motile cilia anomalies. |
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| Skeletal dysplasia v1.142 | INTS13 |
Zornitza Stark gene: INTS13 was added gene: INTS13 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: INTS13 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: INTS13 were set to 36229431 Phenotypes for gene: INTS13 were set to orofaciodigital syndrome, MONDO:0015375, INTS13-related Review for gene: INTS13 was set to GREEN Added comment: PMID 36229431 reports 4 individuals from 2 families with autosomal recessive oral‑facial‑digital syndrome type 2 (OFD2) caused by homozygous loss‑of‑function INTS13 variants; affected individuals present with cleft lip, craniofacial dysmorphism, digital anomalies and short stature. Sources: Literature |
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| Skeletal dysplasia v1.140 | CYP3A4 |
Zornitza Stark gene: CYP3A4 was added gene: CYP3A4 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: CYP3A4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CYP3A4 were set to 38179381; 36656330; 29461981 Phenotypes for gene: CYP3A4 were set to vitamin D-dependent rickets, type 3, MONDO:0033640 Review for gene: CYP3A4 was set to AMBER Added comment: Four families with the CYP3A4 c.902T>C (p.Ile301Thr) missense variant reported presenting with vitamin D‑dependent rickets type 3 (VDDR3), a childhood‑onset disorder characterised by rickets, growth arrest, bone deformities and accelerated vitamin D metabolite inactivation. The variant shows gain‑of‑function activity in vitro, and the disease is treatable with high‑dose vitamin D therapy. Amber rating as all families have had the same variant. Different ethnic backgrounds make founder effect unlikely. Sources: Literature |
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| Skeletal dysplasia v1.138 | MAP3K20 |
Zornitza Stark gene: MAP3K20 was added gene: MAP3K20 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MAP3K20 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MAP3K20 were set to 39648035; 38451290; 32266845; 32266845; 26755636; 26755636 Phenotypes for gene: MAP3K20 were set to split-foot malformation-mesoaxial polydactyly syndrome, MONDO:0014816 Review for gene: MAP3K20 was set to GREEN Added comment: Split hand‑foot malformation with ectodermal dysplasia, craniosynostosis and sensorineural hearing loss (dominant): PMID 38451290 reports five families and PMID 39648035 reports one family with de novo heterozygous MAP3K20 variants, totalling six families. Split‑foot malformation‑mesoaxial polydactyly syndrome (recessive): PMID 26755636 describes two unrelated consanguineous families (five patients) with homozygous loss‑of‑function MAP3K20 variants. Sources: Literature |
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| Skeletal dysplasia v1.136 | HMGB1 |
Zornitza Stark gene: HMGB1 was added gene: HMGB1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: HMGB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: HMGB1 were set to 36755093; 34159400 Phenotypes for gene: HMGB1 were set to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905 Review for gene: HMGB1 was set to GREEN Added comment: PMID 34159400 reports 1 individual with a de novo heterozygous frameshift HMGB1 variant causing severe mirror‑image foot polydactyly, a monogenic autosomal‑dominant condition. PMID 36755093 reports 5 individuals from 5 families with de novo heterozygous frameshift HMGB1 variants causing Brachyphalangy, Polydactyly and Tibial Aplasia syndrome (BPTAS). Sources: Literature |
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| Skeletal dysplasia v1.132 | IQCE |
Zornitza Stark gene: IQCE was added gene: IQCE was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: IQCE was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IQCE were set to 38818822; 31549751; 28488682 Phenotypes for gene: IQCE were set to postaxial polydactyly type A, MONDO:0019673 Review for gene: IQCE was set to GREEN Added comment: Five families (ten individuals) reported with biallelic IQCE variants and postaxial polydactyly. Sources: Literature |
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| Skeletal dysplasia v1.129 | FOXI3 |
Zornitza Stark gene: FOXI3 was added gene: FOXI3 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: FOXI3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: FOXI3 were set to 41639043; 40128339; 37041148; 36260083 Phenotypes for gene: FOXI3 were set to craniofacial microsomia 2, MONDO:0958194 Review for gene: FOXI3 was set to GREEN Added comment: Over 20 families reported, this is a type of mandibulofacial dysostosis. Sources: Literature |
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| Skeletal dysplasia v1.127 | CPLANE2 |
Zornitza Stark gene: CPLANE2 was added gene: CPLANE2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: CPLANE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CPLANE2 were set to 40593758; 39386566 Phenotypes for gene: CPLANE2 were set to Ciliopathy, MONDO:0005308, CPLANE2-related Review for gene: CPLANE2 was set to GREEN Added comment: PMID 40593758 reports three individuals from unrelated families with biallelic loss-of-function CPLANE2 variants and oral‑facial‑digital syndrome, a syndrome featuring cleft palate, tongue lobulation, pre‑ and post‑axial polydactyly, renal cystic dysplasia and occasional cardiac defects. Variant‑specific functional assays in Xenopus demonstrate disrupted basal‑body docking and impaired IFT‑A2 recruitment. Ciliopathy with skeletal manifestations. Sources: Literature |
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| Skeletal dysplasia v1.125 | COPB2 |
Zornitza Stark gene: COPB2 was added gene: COPB2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: COPB2 were set to 34450031 Phenotypes for gene: COPB2 were set to Osteoporosis, childhood- or juvenile-onset, with developmental delay, MIM# 619884 Review for gene: COPB2 was set to GREEN Added comment: PMID 34450031 reports four unrelated heterozygous loss-of-function variants across four families causing early‑onset osteoporosis, fractures and developmental delay (Monoallelic). Additionally, two siblings homozygous for a missense variant in a fifth family present with microcephaly, severe developmental delay and low bone mass (Biallelic). Sources: Literature |
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| Skeletal dysplasia v1.123 | ATRIP |
Zornitza Stark gene: ATRIP was added gene: ATRIP was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: ATRIP was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATRIP were set to 40029331 Phenotypes for gene: ATRIP were set to Seckel syndrome, MONDO:0019342, ATRIP-related Review for gene: ATRIP was set to GREEN Added comment: PMID 40029331 reports 3 individuals from three families with biallelic ATRIP splice variants presenting with microcephalic primordial dwarfism and combined immunodeficiency. Affected individuals exhibit severe intrauterine growth restriction, post‑natal short stature, microcephaly and recurrent infections. Sources: Literature |
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| Skeletal dysplasia v1.112 | TK1 |
chirag patel gene: TK1 was added gene: TK1 was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: TK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: TK1 were set to Thoracolaryngopelvic dysplasia, MONDO:0008551 Review for gene: TK1 was set to AMBER Added comment: ESHG 2026 Barnes syndrome (thoraco-laryngo-pelvic dysplasia/TLPD) is a very rare autosomal dominant skeletal dysplasia, clinically characterised by thoracic dystrophy, narrow pelvis and laryngeal stenosis. They report 3 unrelated individuals with TLPD with neonatal hypotonia, thoracic dystrophy with short ribs, subglottic stenosis/tracheal hypoplasia requiring tracheostomy, and narrow pelvis with delayed ossification of pubic rami. Trio WGS identified 2 different rare heterozygous de novo variants (1 x p.Phe29Leu and 2 x p.Lys170del) in TK1 gene. TK1 gene codes for cytosolic thymidine kinase, which phosphorylates thymidine and plays role in DNA synthesis and cell proliferation. Functional studies in lymphoblastoid cell lines suggest a significant reduction of TK1 activity. Further studies are needed to clarify the role of TK1 in bone morphogenesis. Sources: Other |
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| Skeletal dysplasia v1.106 | PRDM1 |
chirag patel gene: PRDM1 was added gene: PRDM1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PRDM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRDM1 were set to 38456586; 37083955 Phenotypes for gene: PRDM1 were set to Split hand-foot malformation MONDO:0016576, PRDM1-related Review for gene: PRDM1 was set to GREEN Added comment: PMID 38456586 (and PMID 37083955) report 3 families with split hand/foot malformation (SHFM) caused by heterozygous PRDM1 variants. The frameshift variant (c.712_713insT) segregated in a multigenerational family (3 affected individuals) with variable penetrance (2 unaffected individuals). The 2 missense variants (p.T524R and p.T819A) were de novo (but the p.T819A variant exceeds population‑frequency thresholds). Zebrafish rescue assays showing loss‑of‑function, as wild‑type human PRDM1 rescues fin defects, whereas each mutant mRNA fails to rescue. Sources: Literature |
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| Skeletal dysplasia v1.104 | SCNM1 |
chirag patel changed review comment from: PMID 36084634 and PMID 41291844 report a total of 9 individuals from 7 independent consanguineous families with biallelic loss‑of‑function SCNM1 variants presenting with orofaciodigital syndrome 19. Clinical features included: bilateral postaxial polydactyly, foot syndactyly, short limbs, tongue hamartomas, micro/retrognathia, arched/cleft palate, hypo/microdontia with missing incisors, talipes equinovarus, delayed speech and brain anomalies. Variants were frameshift, missense, splice, and AluYc1 sequence insertion) with segregation confirmed in all families. Functional studies including a minigene splice assay, SCNM1 knock‑out/knock‑down in RPE‑1 cells and patient‑fibroblast rescue experiments demonstrate reduced SCNM1 protein, defective U12‑type intron splicing, elongated primary cilia and impaired Hedgehog signalling, confirming loss‑of‑function as the disease mechanism. Sources: Literature; to: PMID 36084634 and PMID 41291844 report a total of 9 individuals from 7 independent consanguineous families with biallelic loss‑of‑function SCNM1 variants presenting with orofaciodigital syndrome 19. Clinical features included: bilateral postaxial polydactyly, foot syndactyly, bifid halluces, short limbs, tongue hamartomas, micro/retrognathia, arched/cleft palate, hypo/microdontia with missing incisors, talipes equinovarus, developmental delay and brain anomalies. Variants were frameshift, missense, splice, and AluYc1 sequence insertion) with segregation confirmed in all families. Functional studies including a minigene splice assay, SCNM1 knock‑out/knock‑down in RPE‑1 cells and patient‑fibroblast rescue experiments demonstrate reduced SCNM1 protein, defective U12‑type intron splicing, elongated primary cilia and impaired Hedgehog signalling, confirming loss‑of‑function as the disease mechanism. Sources: Literature |
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| Skeletal dysplasia v1.104 | SCNM1 |
chirag patel changed review comment from: PMID 36084634 and PMID 41291844 report a total of 5 individuals from 4 independent consanguineous families with biallelic loss‑of‑function SCNM1 variants presenting with orofaciodigital syndrome 19, a disorder characterised by oral, facial and digital anomalies, limb shortening, polydactyly, tibial hemimelia and neurodevelopmental delay. Variants were frameshift, missense, splice, and AluYc1 sequence insertion) with segregation confirmed in all families. Functional studies including a minigene splice assay, SCNM1 knock‑out/knock‑down in RPE‑1 cells and patient‑fibroblast rescue experiments demonstrate reduced SCNM1 protein, defective U12‑type intron splicing, elongated primary cilia and impaired Hedgehog signalling, confirming loss‑of‑function as the disease mechanism. Sources: Literature; to: PMID 36084634 and PMID 41291844 report a total of 9 individuals from 7 independent consanguineous families with biallelic loss‑of‑function SCNM1 variants presenting with orofaciodigital syndrome 19. Clinical features included: bilateral postaxial polydactyly, foot syndactyly, short limbs, tongue hamartomas, micro/retrognathia, arched/cleft palate, hypo/microdontia with missing incisors, talipes equinovarus, delayed speech and brain anomalies. Variants were frameshift, missense, splice, and AluYc1 sequence insertion) with segregation confirmed in all families. Functional studies including a minigene splice assay, SCNM1 knock‑out/knock‑down in RPE‑1 cells and patient‑fibroblast rescue experiments demonstrate reduced SCNM1 protein, defective U12‑type intron splicing, elongated primary cilia and impaired Hedgehog signalling, confirming loss‑of‑function as the disease mechanism. Sources: Literature |
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| Skeletal dysplasia v1.103 | SCNM1 |
chirag patel gene: SCNM1 was added gene: SCNM1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: SCNM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCNM1 were set to 41291844; 36084634 Phenotypes for gene: SCNM1 were set to Orofaciodigital syndrome 19, MONDO:0859310 Review for gene: SCNM1 was set to GREEN Added comment: PMID 36084634 and PMID 41291844 report a total of 5 individuals from 4 independent consanguineous families with biallelic loss‑of‑function SCNM1 variants presenting with orofaciodigital syndrome 19, a disorder characterised by oral, facial and digital anomalies, limb shortening, polydactyly, tibial hemimelia and neurodevelopmental delay. Variants were frameshift, missense, splice, and AluYc1 sequence insertion) with segregation confirmed in all families. Functional studies including a minigene splice assay, SCNM1 knock‑out/knock‑down in RPE‑1 cells and patient‑fibroblast rescue experiments demonstrate reduced SCNM1 protein, defective U12‑type intron splicing, elongated primary cilia and impaired Hedgehog signalling, confirming loss‑of‑function as the disease mechanism. Sources: Literature |
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| Skeletal dysplasia v1.100 | TXNDC15 |
chirag patel gene: TXNDC15 was added gene: TXNDC15 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: TXNDC15 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TXNDC15 were set to 41518077; 39679447; 38156946; 38073519; 31411728; 30851085; 27894351 Phenotypes for gene: TXNDC15 were set to Meckel syndrome 14, MIM# 619879 Review for gene: TXNDC15 was set to GREEN Added comment: PMID 41518077, PMID 38073519, PMID 38156946, PMID 30851085, PMID 31411728 and PMID 27894351 report 8 families with biallelic loss‑of‑function TXNDC15 variants causing Meckel syndrome, a perinatally lethal autosomal recessive ciliopathy characterised by occipital encephalocele, polycystic kidneys, postaxial polydactyly and omphalocele. Segregation, ultra‑rare population frequencies and functional studies in patient cells and mouse models support the association. Sources: Literature |
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| Skeletal dysplasia v1.95 | VPS16 |
chirag patel gene: VPS16 was added gene: VPS16 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS16 were set to 34013567; 33938619 Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis or mucopolysaccharidosis-like disorder, MONDO:0100365 Review for gene: VPS16 was set to GREEN Added comment: PMID 34013567 reports a consanguineous Turkish‑Arab family with two siblings homozygous for a missense VPS16 p.Trp180Cys variant presenting with a mucopolysaccharidosis‑like multisystem disorder that includes short stature, coarse facies, spondylar dysplasia and severe neutropenia. PMID 33938619 identifies two unrelated families harbouring a homozygous intronic splice‑site c.2272-18C>A variant that causes a similar early‑onset mucopolysaccharidosis‑like disease with dysostosis multiplex, neurodevelopmental regression and hematological abnormalities. Functional studies show ~85 % loss of VPS16 protein in patient fibroblasts rescued by wild‑type VPS16 expression and a vps16‑deficient zebrafish recapitulating the neuro‑developmental and lysosomal phenotypes. Sources: Literature |
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| Skeletal dysplasia v1.70 | VCP |
chirag patel changed review comment from: Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). PMID 41979051 reports 7 families with Adams-Oliver syndrome and rare heterozygous missense VCP variants (4 de novo, 2 inherited from affected parent, 1 presumed inherited). Variant‑specific functional assays support pathogenicity as they were hypermorphic for ATPase activity. Pulmonary hypertension seen in 5/7 families. 3 families had features of multisystem proteinopathy 1 (MSP1) - progressive myopathy (2 families), neuropathy (1 family), lytic bone lesions (1 family), and frontotemporal dementia (1 family) - and had offspring with AOS and severe or fatal PH, suggesting these conditions form a spectrum of VCP-related disease. Sources: Literature; to: Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). PMID 41979051 reports 7 families with Adams-Oliver syndrome and rare heterozygous missense VCP variants (4 de novo, 2 inherited from affected parent, 1 presumed inherited). Variant‑specific functional assays support pathogenicity as they were hypermorphic for ATPase activity. Congenital heart defects seen in 6/7 and pulmonary hypertension seen in 5/7 families. 3 families had features of multisystem proteinopathy 1 (MSP1) - progressive myopathy (2 families), neuropathy (1 family), lytic bone lesions (1 family), and frontotemporal dementia (1 family) - and had offspring with AOS and severe or fatal PH, suggesting these conditions form a spectrum of VCP-related disease. Sources: Literature |
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| Skeletal dysplasia v1.69 | VCP |
chirag patel gene: VCP was added gene: VCP was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VCP were set to 41979051 Phenotypes for gene: VCP were set to Adams-Oliver syndrome MONDO:0007034, VCP-related Review for gene: VCP was set to GREEN Added comment: Adams-Oliver syndrome (AOS) is a rare developmental disorder defined by the combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly). PMID 41979051 reports 7 families with Adams-Oliver syndrome and rare heterozygous missense VCP variants (4 de novo, 2 inherited from affected parent, 1 presumed inherited). Variant‑specific functional assays support pathogenicity as they were hypermorphic for ATPase activity. Pulmonary hypertension seen in 5/7 families. 3 families had features of multisystem proteinopathy 1 (MSP1) - progressive myopathy (2 families), neuropathy (1 family), lytic bone lesions (1 family), and frontotemporal dementia (1 family) - and had offspring with AOS and severe or fatal PH, suggesting these conditions form a spectrum of VCP-related disease. Sources: Literature |
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| Skeletal dysplasia v1.65 | chirag patel Copied gene SGMS2 from panel Osteogenesis Imperfecta and Osteoporosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.63 | RNU12 |
chirag patel gene: RNU12 was added gene: RNU12 was added to Skeletal dysplasia. Sources: Expert Review Green,Literature non-coding gene tags were added to gene: RNU12. Mode of inheritance for gene: RNU12 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNU12 were set to 34085356; 27863452 Phenotypes for gene: RNU12 were set to Craniosynostosis-anal anomalies-porokeratosis syndrome MONDO:0011287 |
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| Skeletal dysplasia v1.56 | PORCN | chirag patel Marked gene: PORCN as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.56 | PORCN | chirag patel Gene: porcn has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.56 | chirag patel Copied gene PORCN from panel Mendeliome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.56 | PORCN |
chirag patel gene: PORCN was added gene: PORCN was added to Skeletal dysplasia. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: PORCN was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: PORCN were set to Focal dermal hypoplasia, MIM# 305600 |
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| Skeletal dysplasia v1.48 | MBTPS2 |
chirag patel gene: MBTPS2 was added gene: MBTPS2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MBTPS2 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: MBTPS2 were set to 37305034; 34093655; 27380894 Phenotypes for gene: MBTPS2 were set to Osteogenesis imperfecta, type 19, MONDO:0049223 Review for gene: MBTPS2 was set to GREEN Added comment: PMID 27380894 and PMID 37305034 report X-linked osteogenesis imperfecta caused by MBTPS2 missense variants. PMID 27380894 describes 8 affected individuals from two unrelated families with variants p.N459S and p.L505F; PMID 37305034 adds a third family with a p.Glu172Asp variant and includes the earlier families as controls. All three families present prenatal fractures, short stature, bowing of long bones, scoliosis and blue/white sclerae. Patient fibroblasts/osteoblasts show impaired regulated intramembrane proteolysis, reduced type I collagen secretion and altered ER morphology. CHO‑M19 luciferase reporter assays demonstrate reduced ATF6 activation. RNA‑seq, lipidomic profiling and electron microscopy reveal transcriptomic and cellular deficits. qRT‑PCR of bone‑development genes and immunocytochemistry show reduced collagen deposition. Sources: Literature |
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| Skeletal dysplasia v1.46 | KIAA0825 |
chirag patel gene: KIAA0825 was added gene: KIAA0825 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: KIAA0825 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0825 were set to 41010063; 37107627; 35886013; 32147526; 30982135 Phenotypes for gene: KIAA0825 were set to Postaxial polydactyly type A, MONDO:0019673 Review for gene: KIAA0825 was set to GREEN Added comment: PMID 30982135 reports 6 individuals from 2 families, PMID 32147526 reports 2 individuals from 1 family, PMID 35886013 reports a prenatally detected case (1 individual, 1 family), PMID 37107627 reports 2 individuals from 1 family, and PMID 41010063 reports 10 individuals from 4 families, totalling 21 patients from 9 families (8 independent) with autosomal recessive postaxial polydactyly type A. Mouse knockout shows reduced bone mineral density (PMID 30982135, PMID 41010063); minigene splice assays demonstrate loss‑of‑function for splice variants (PMID 35886013); protein structural modelling predicts destabilisation for missense variants (PMID 32147526, PMID 37107627, PMID 41010063). Sources: Literature |
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| Skeletal dysplasia v1.43 | IL6ST |
chirag patel gene: IL6ST was added gene: IL6ST was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: IL6ST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL6ST were set to 40835206; 38133879; 31914175 Phenotypes for gene: IL6ST were set to Stuve-Wiedemann syndrome 2, MONDO:0030756 Review for gene: IL6ST was set to GREEN Added comment: PMID 38133879, PMID 31914175 and PMID 40835206 together report 11 individuals from 7 families with homozygous truncating or splice IL6ST variants presenting with bent long bones, respiratory failure and perinatal lethality. Patient‑derived cells (amniocytes, EBV‑LCLs) lack GP130 surface expression and IL‑6/IL‑11 signalling, rescued by lentiviral WT GP130 (PMID 31914175). HEK293 GP130‑KO cells transfected with mutant constructs fail to signal (PMID 31914175). Sources: Literature |
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| Skeletal dysplasia v1.25 | POLR3A |
chirag patel gene: POLR3A was added gene: POLR3A was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLR3A were set to 30414627, 30450527, 30323018, 21671373, 10607952 Phenotypes for gene: POLR3A were set to Wiedemann-Rautenstrauch syndrome, MONDO:0009910 Review for gene: POLR3A was set to GREEN Added comment: Multiple families reported with biallelic variants in POLR3A and Wiedemann-Rautenstrauch syndrome (WDRTS). This is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, generalized lipoatrophy, various skeletal anomalies, hypotonia, and variable mental impairment. Sources: Literature |
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| Skeletal dysplasia v1.24 | WLS |
chirag patel gene: WLS was added gene: WLS was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WLS were set to 40618129; 34587386 Phenotypes for gene: WLS were set to Zaki syndrome, MONDO:0859209 Review for gene: WLS was set to GREEN Added comment: PMID 34587386 reports 10 individuals from five families (three independent families with qualifying homozygous WLS missense variants) and PMID 40618129 reports 1 individual from a further independent family with compound heterozygous WLS variants, together defining Zaki syndrome – a multisystem congenital disorder featuring microcephaly, facial dysmorphism, foot syndactyly, renal agenesis/hydronephrosis, cardiac defects, short stature and developmental delay. Functional studies including protein loss, impaired Wnt secretion, knock‑in mouse models and rescue with the Wnt agonist CHIR99021 support a loss‑of‑function mechanism. Skeletal anomalies included toe syndactyly, ectrodactyly, broad distal phalanges, long fingers, and hypoplasia of toe phalanges and toenails. Sources: Literature |
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| Skeletal dysplasia v1.18 | CDK10 |
chirag patel gene: CDK10 was added gene: CDK10 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: CDK10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CDK10 were set to 41836559; 40960173; 36503922; 34369103; 28886341 Phenotypes for gene: CDK10 were set to Al Kaissi syndrome, MONDO:0044324 Review for gene: CDK10 was set to GREEN Added comment: Multiple individuals from unrelated families reported with biallelic loss-of-function CDK10 variants (splice-site or frameshift) presenting with Al Kaissi syndrome. This is an autosomal recessive developmental disorder characterized by growth retardation, spine malformation particularly of the cervical spine (including clefting, segmentation anomalies, and improper fusion), dysmorphic facial features, and delayed psychomotor development with moderate to severe intellectual disability. Mouse osteoblast‑specific Cdk10 knockout recapitulates skeletal phenotype. Sources: Literature |
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| Skeletal dysplasia v1.4 | SLC13A1 | Zornitza Stark edited their review of gene: SLC13A1: Added comment: PMID 36175384: additional report of an affected individual homozygous for the p.(Arg12*) variant, which has 7 homs in gnomAD v4.; Changed publications: 39925707, 36175384; Changed phenotypes: Hyposulfatemia with skeletal dysplasia, MIM# 621654 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.1 | ID4 downstream regulatory region |
Sarah Milton Region: ID4 downstream regulatory region was added Region: ID4 downstream regulatory region was added to Skeletal dysplasia. Sources: Literature regulatory region tags were added to Region: ID4 downstream regulatory region. Mode of inheritance for Region: ID4 downstream regulatory region was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for Region: ID4 downstream regulatory region were set to 42069959; 26032025; 24628666 Phenotypes for Region: ID4 downstream regulatory region were set to Mesomelic dysplasia, Savarirayan type, MIM#605274 Review for Region: ID4 downstream regulatory region was set to GREEN Added comment: ID4 encodes inhibitor of DNA binding 4 (ID4) protein which modulates gene expression through binding to and inhibiting bHLH transcription factors. It is involved in regulation of cellular growth, senescence, differentiation and apoptosis. It is known to be expressed in the developing limb bud. PMID: 42069959, 26032025, 24628666 report a total of 5 individuals with de novo structural variants (deletions of around 2mb in size and one inversion) affecting the region downstream of ID4 at 6p22.3. The clinical presentation of these individuals was that of Mesomelic dysplasia, Savarirayan type characterised by mesomelic shortening of the lower limbs with the upper limbs affected in some individuals and specific radiographic findings. The deletions encompassed 4 protein coding genes none of which are involved in skeletal development. As such it was hypothesized these structural variants disrupt TADs resulting in ID4 dysregulation, bringing the gene in closer proximity to a cluster of enhancers downstream. Deletions involving the ID4 gene did not recapitulate the phenotype, as such, dysregulated expression as opposed to loss of function is thought to be the mechanism. There are no equivalent deletions in population databases (gnomAD/DGV gold) Hi-C studies have been performed however functional studies using luciferase reporter assays/qPCR of ID4 have not yet been published. Note: Coordinates used for this entry are that of the smallest reported deletion. Sources: Literature |
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| Skeletal dysplasia v1.0 | POR | Gene migrated from ENSG00000127948 to ENSG00000127948 (gene set migration) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.450 | PFN1 |
Zornitza Stark gene: PFN1 was added gene: PFN1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PFN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PFN1 were set to 33599011; 32392277; 31991009; 31346562 Phenotypes for gene: PFN1 were set to Paget disease of bone 7, early-onset, MIM# 621600 Review for gene: PFN1 was set to AMBER Added comment: Three multiplex families reported with same variant, c.318_321delTGAC, and Paget's disease of bone. Two are from the same region in Italy, whereas the third is Chinese, making a founder variant less likely. Functional studies of this truncating variant showed abnormal protein aggregates (PMID: 32392277, 31991009). An osteoclast-specific conditional null mouse model confirmed the skeletal phenotype (PMID: 31346562). Sources: Literature |
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| Skeletal dysplasia v0.447 | Zornitza Stark Copied gene CCDC134 from panel Osteogenesis Imperfecta and Osteoporosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.445 | APC |
Zornitza Stark gene: APC was added gene: APC was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: APC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: APC were set to 30237576; 28383543; 25676610 Phenotypes for gene: APC were set to Syndromic disease, MONDO:0002254, APC-related Review for gene: APC was set to RED Added comment: PMID 25676610 reports 4 individuals from a Saudi consanguineous family with a homozygous APC splice‑site deletion and Cenani‑Lenz syndrome; PMID 28383543 reports another Saudi with homozygous APC splice‑site deletion and CLS; PMID 30237576 reports another Saudi individual with splice-site variant and CLS. All present with congenital limb malformations, syndactyly and scoliosis. Likely founder variant. Possible multiple reports of same family. All part of large cohorts with minimal additional information or functional validation, hence RED rating. Sources: Literature |
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| Skeletal dysplasia v0.443 | CWC27 | Zornitza Stark changed review comment from: Highly variable phenotype characterised by RP and brachydactyly. RP is slowly progressive, with night blindness occurring around 10 years of age (one individual reported with much more severe LCA phenotype). Additional features present in many individuals including frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears. Neurologic features included delays in speech, feeding, and walking, as well as intellectual disability (mild to moderate range). Congenital anomalies affecting heart/kidneys reported. Eight unrelated families reported.; to: Highly variable phenotype characterised by RP and metaphyseal chondrodysplasia, typically brachydactyly. RP is slowly progressive, with night blindness occurring around 10 years of age (one individual reported with much more severe LCA phenotype). Additional features present in many individuals including frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears. Neurologic features included delays in speech, feeding, and walking, as well as intellectual disability (mild to moderate range). Congenital anomalies affecting heart/kidneys reported. Eight unrelated families reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.437 | CENPJ |
Zornitza Stark gene: CENPJ was added gene: CENPJ was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: CENPJ was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CENPJ were set to 34068194 Phenotypes for gene: CENPJ were set to Seckel syndrome 4, MIM# 613676 Review for gene: CENPJ was set to AMBER Added comment: PMID 34068194 reports 3 individuals from 2 unrelated families with autosomal recessive homozygous CENPJ variants presenting with Seckel syndrome. Functional assays (RT‑PCR splice assay, immunoblot, immunofluorescence) demonstrate aberrant splicing, reduced CENPJ protein and centrosome amplification, supporting pathogenicity. Sources: Literature |
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| Skeletal dysplasia v0.429 | AIFM1 |
Zornitza Stark gene: AIFM1 was added gene: AIFM1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: AIFM1 were set to 33439541; 28842795; 27102849 Phenotypes for gene: AIFM1 were set to spondyloepimetaphyseal dysplasia, Bieganski type, MONDO:0010275; Spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, MIM# 300232 Review for gene: AIFM1 was set to GREEN Added comment: PMID 28842795 reports 12 affected males from 6 unrelated families with X‑linked AIFM1 variants; PMID 27102849 reports 7 affected males from 2 unrelated families with the recurrent p.Asp237Gly variant; PMID 33439541 adds 2 affected males from 2 families (one novel intronic splice variant, one previously reported synonymous variant). All cases present with short stature, kyphoscoliosis, spondylometaphyseal dysplasia, cerebral hypomyelination, motor delay and progressive neurodegeneration. Functional studies show reduced AIFM1 mRNA/protein and exon‑7 skipping, supporting loss‑of‑function. X‑linked recessive inheritance with carrier mothers (occasionally mosaic) is consistently reported. Sources: Literature |
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| Skeletal dysplasia v0.422 | KIF22 |
Zornitza Stark edited their review of gene: KIF22: Added comment: PMID 38477767 reports six individuals from six unrelated families (three with a homozygous c.146G>A p.Arg49Gln recessive variant and three with heterozygous c.443C>T p.Pro148Leu or c.446G>A p.Arg149Gln dominant variants) presenting with spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto‑SEMDJL). All patients display short stature, generalized joint laxity, multiple dislocations, scoliosis, and characteristic radiographic findings. Evidence for recessive disease is limited to the one variant, albeit in three families (?founder).; Changed publications: 25256152, 38477767; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
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| Skeletal dysplasia v0.410 | GDF3 | Zornitza Stark edited their review of gene: GDF3: Added comment: Single family reported in 2010 with this phenotype, none since. Note ocular abnormalities also present so unsure if this is a distinct disorder.; Changed phenotypes: Klippel-Feil anomaly with laryngeal malformation - 613702 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.401 | ARCN1 | Zornitza Stark changed review comment from: 4 unrelated families reported.; to: At least 14 individuals reported, summarised in PMID 35300924. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.395 | MIR17HG |
Zornitza Stark changed review comment from: 4 unrelated cases reported - 3 with gene deletions, 1 with SNV Sources: Expert list; to: 4 unrelated cases reported - 3 with gene deletions, 1 with SNV. The deletions include portion of GPC5 as well. Sources: Expert list |
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| Skeletal dysplasia v0.394 | TMEM251 |
Zornitza Stark changed review comment from: PMID 40171858: reports 2 siblings from an Iranian consanguineous family and six previously reported families (8 patients, 7 unrelated families) with biallelic loss‑of‑function LYSET variants presenting with MLII‑like mucolipidosis; core features include dysostosis multiplex, coarse facial features, hepatomegaly, joint contractures, developmental delay; mouse knockout recapitulates the phenotype, supporting gene‑disease causality.; to: PMID 40171858: reports 2 siblings from an Iranian consanguineous family and six previously reported families (8 patients, 7 unrelated families) with biallelic loss‑of‑function LYSET variants presenting with MLII‑like mucolipidosis; core features include dysostosis multiplex, coarse facial features, hepatomegaly, joint contractures, developmental delay; mouse knockout recapitulates the phenotype, supporting gene‑disease causality. HGNC approved name is LYSET. |
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| Skeletal dysplasia v0.392 | TMEM251 | Zornitza Stark commented on gene: TMEM251: PMID 40171858: reports 2 siblings from an Iranian consanguineous family and six previously reported families (8 patients, 7 unrelated families) with biallelic loss‑of‑function LYSET variants presenting with MLII‑like mucolipidosis; core features include dysostosis multiplex, coarse facial features, hepatomegaly, joint contractures, developmental delay; mouse knockout recapitulates the phenotype, supporting gene‑disease causality. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.384 | NMNAT1 |
chirag patel gene: NMNAT1 was added gene: NMNAT1 was added to Skeletal dysplasia. Sources: Expert List Mode of inheritance for gene: NMNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NMNAT1 were set to 32533184, 33668384 Phenotypes for gene: NMNAT1 were set to Spondyloepiphyseal dysplasia, sensorineural hearing loss, intellectual disability, and Leber congenital amaurosis (SHILCA), MIM#619260 Review for gene: NMNAT1 was set to AMBER Added comment: 3 families reported, but 2 are distantly related (shared haplotype). Clinical presentation was severe spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA). The affected children in the 2 related families were homozygous for 7.4-kb duplication involving the last 2 exons of the NMNAT1 gene, spanning the beginning of intron 3 to the middle of the 3-prime UTR (chr1:10,036,359-10,043,727, GRCh37). The third affected individual was compound het for the duplication and a splicing variant. mRNA expression assays detected aberrant alternative transcripts and unbalanced levels of expression. Sources: Expert List |
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| Skeletal dysplasia v0.362 | COL10A1 |
Zornitza Stark changed review comment from: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher). Note that unlike with other collagens, Gly-X-Y substitutions in the collagen triple helix repeats are very rarely reported as disease-causing, and may result in a milder phenotype (PMID 31348255; 25542771). These should be interpreted with caution.; to: Note that unlike with other collagens, Gly-X-Y substitutions in the collagen triple helix repeats are very rarely reported as disease-causing, and may result in a milder phenotype (PMID 31348255; 25542771). These should be interpreted with caution. |
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| Skeletal dysplasia v0.362 | COL10A1 |
Zornitza Stark changed review comment from: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher), however please note that to date, no Gly-X-Y substitutions in the collagen triple helix repeats have yet been reported, pathogenic or otherwise.; to: Note: Gene reviews also notes severe lethal phenotypes in recessive inheritance where parents were only mildly affected, however only 2 unrelated families reported to date (PMID: 31633898). Both haploinsufficiency and dominant-negative mechanisms have been suggested to cause disease (OMIM, PMID: 15880705, PMID: 31633898). “Pathogenic variants in COL10A1 are clustered in the C-terminal non-collagenous (NC1) domain, which contains motifs required for normal assembly of the collagen trimer. Both missense and truncating (frameshift and nonsense) variants in COL10A1 cause collagen X protein misfolding during protein synthesis, resulting in a failure of trimerization and aggregation within the endoplasmic reticulum (ER) of hypertrophic chondrocytes. Resultant ER stress, activation of the unfolded protein response, and reduced levels of functional type X collagen in the growth plate cause chondrodysplasia and development of the SMCD phenotype [Rajpar et al 2009].” -> from Gene Reviews (PMID: 31633898). Some pathogenic missense also reported in the N-terminal signal peptide (Decipher). Note that unlike with other collagens, Gly-X-Y substitutions in the collagen triple helix repeats are very rarely reported as disease-causing, and may result in a milder phenotype (PMID 31348255; 25542771). These should be interpreted with caution. |
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| Skeletal dysplasia v0.360 | ADAMTSL2 | Zornitza Stark edited their review of gene: ADAMTSL2: Added comment: PMID 36896612: 12 individuals reported with the severe end of the spectrum of ADAMTSL2-related skeletal dysplasia. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly.; Changed publications: 33369194, 26879370, 21415077, 36896612; Changed phenotypes: Geleophysic dysplasia 1, MIM# 231050, Dermatosparaxic Ehlers Danlos syndrome, Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.337 | DDR2 |
chirag patel Source Victorian Clinical Genetics Services was removed from DDR2. Source ClinGen was added to DDR2. Phenotypes for gene: DDR2 were changed from Spondylometaepiphyseal dysplasia, short limb-hand type 271665; Spondylometaepiphyseal dysplasia, short limb-hand type 271665, at least 3 cases reported to Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome, MONDO:0010077 Publications for gene DDR2 were changed from 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 to 19110212, 20223752, 24725993, 31406622, 33953858, 29884795, 35221872 |
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| Skeletal dysplasia v0.332 | DMRT2 | Krithika Murali edited their review of gene: DMRT2: Added comment: PMID: 29681102 Bouman et al 2018 paper SH3PXD2B reviewed - not coding in canonical transcript, 4 homs in gnomAD v4. In summary, 2 unrelated individuals with severe skeletal dysplasia and other extra-skeletal features and one mouse model with severe skeletal dysplasia supporting Green classification.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.330 | DMRT2 |
Krithika Murali gene: DMRT2 was added gene: DMRT2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: DMRT2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DMRT2 were set to PMID: 41014130; 29681102; 16387292 Phenotypes for gene: DMRT2 were set to skeletal dysplasia MONDO:0018230; DMRT2-related Review for gene: DMRT2 was set to AMBER Added comment: PMID: 41014130 Rips et al 2025 report a newborn of consanguineous non-AJ ancestry with severe costovertebral malformations, dysmorphism and homozygous LoF DMRT2 variant identified on singleton exome sequencing (no parental testing). The patient also had congenital heart disease, bilateral duplicated kidneys, cleft palate, inguinal hernias.This patient also had immunodeficiency with thymic aplasia, absence of TRECs on NBS, profound lymphopenia with death at 3 months of age from CMV pneumonitis. Prenatal features include severe polyhydramnios. PMID: 29681102 Bouman et al 2018 report a male neonate of consanguineous North African descent with thoracic vertebral anomalies, rib anomalies, dysmorphism and severe respiratory deficiency resulting in neonatal death at 9 days of age. Extra-skeletal anomalies included aberrate right subclavian artery, non-functional left kidney and tetehterd cord.Prenatal features included increased NT (8.0mm), scoliosis (15+4 weeks), IUGR/kyphoscoliosis/small thoracic cage (28+2 weeks). Trio WES identified a homozygous start-loss DMRT2 variant (c.1A>T p.Met1?) classified as a VUS. In addition, a homozygous canonical acceptor site variant in the non-canonical transcript was detected in SH3PXD2B associated with Frank-Ter Haar syndrome which is also known to have skeletal features including rarely respiratory failure leading to neonatal death (PMID: 31978614). The parents were heterozygous for both sets of variants and the unaffected sibling was homozygous wild-type. PMID: 16387892 Seo et al 2006 report a knockout mouse model with abnormal rib and sternal development, respiratory insufficiency. Overlapping features between the 2 unrelated patients and the mouse model include severe skeletal manifestations. However, one of the reported cases also had an alternative genomic finding relevant to skeletal issues. Other overlapping features observed in the 2 patients and not in the mouse include congenital heart defects and CAKUT. Sources: Literature |
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| Skeletal dysplasia v0.324 | B9D1 | Zornitza Stark edited their review of gene: B9D1: Added comment: Lumped by ClinGen. Additional cases reported.; Changed rating: GREEN; Changed publications: 24886560, 21493627, 25920555, 40565534, 40933483; Changed phenotypes: Ciliopathy, MONDO:0005308, B9D1-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.319 | TGFB2 |
Zornitza Stark edited their review of gene: TGFB2: Added comment: Second skeletal phenotype associated with variants in this gene: Camurati-Engelmann disease-2 (CAEND2). This is an autosomal dominant disorder characterized by progressive diaphyseal dysplasia, associated with a waddling gait, muscle weakness, and severe leg pain. Bone striations are present in the spine, pelvis, and long tubular bones, with epiphyseal sclerosis. Coarse sclerotic trabeculae are observed in the short tubular bones. Skull involvement may be minimal. Four unrelated families reported in PMIDs 39014191 and 40204055. Variants were de novo in 3 of the families, and segregated with disease in the fourth.; Changed publications: 39014191, 40204055; Changed phenotypes: Loeys-Dietz syndrome 4, MIM# 614816, Camurati-Engelmann disease 2, MIM# 606631 |
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| Skeletal dysplasia v0.318 | ENPP5 |
Zornitza Stark gene: ENPP5 was added gene: ENPP5 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: ENPP5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ENPP5 were set to 40457511 Phenotypes for gene: ENPP5 were set to Skeletal dysplasia, MONDO:0018230, ENPP5-related Review for gene: ENPP5 was set to RED Added comment: Single affected individual reported distinct oro-dental phenotype including premaxillary and gingival overgrowth and hypercementosis and a homozygous missense variant p.Gly58Val, affecting a conserved glycine residue predicted to be within a putative active binding site of the ENPP5 protein. In mice, RNA-seq and immunofluorescence confirmed Enpp5 expression in functional osteoblasts of the maxilla and mandible, periodontal ligament, odontoblasts, and ameloblasts. Sources: Literature |
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| Skeletal dysplasia v0.309 | IFT81 | Zornitza Stark edited their review of gene: IFT81: Added comment: More than 5 families reported with a skeletal ciliopathy.; Changed rating: GREEN; Changed publications: 27666822, 37427975, 32783357 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.303 | MEG3 |
Zornitza Stark gene: MEG3 was added gene: MEG3 was added to Skeletal dysplasia. Sources: Expert list SV/CNV, non-coding gene tags were added to gene: MEG3. Mode of inheritance for gene: MEG3 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed) Publications for gene: MEG3 were set to 33010492; 33746039; 33067531; 38212313 Phenotypes for gene: MEG3 were set to Kagami-Ogata syndrome, MIM# 608149 Review for gene: MEG3 was set to GREEN Added comment: Small deletions of MAG3 reported in multiple patients as one of the mechanisms of disease. Bell-shaped thorax and multiple other skeletal anomalies are a feature. Sources: Expert list |
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| Skeletal dysplasia v0.275 | FUZ |
chirag patel gene: FUZ was added gene: FUZ was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: FUZ was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FUZ were set to PMID: 38702430, 29068549, 34719684 Phenotypes for gene: FUZ were set to Ciliopathy_MONDO_0005308; skeletal ciliopathy Review for gene: FUZ was set to GREEN gene: FUZ was marked as current diagnostic Added comment: FUZ is crucial for the transport of components to the primary cilium and potentially promotes protein complex assembly necessary for downstream cilium formation and function. Previous studies have shown complete knockout of Fuz in a mouse model leads to prenatal lethality, coronal craniosynostosis, micrognathia, facial malformations, eye, and heart defects. Suggested as a skeletal ciliopathy disorder gene. PMID: 38702430 1 individual (from family with 2 affecteds) with orofaciodigital syndrome like phenotype (dysmorphism, bilateral foot preaxial polysyndactyly, right foot postaxial polysyndactyly, broad thumbs, bilateral 5th finger clinodactyly narrow chest, partial AVSD). They found a homozygous missense variant in FUZ [p.(Glu201Lys)]. Parents were heterozygous carriers. A sibling died at 18mths and had complete AVSD, bilateral cleft lip and palate, right 5th finger clinodactyly, and medially deviated/broad great toes. 1 fetus with orofaciodigital syndrome like phenotype (right cleft lip, 4 limb polydactyly, bilateral duplicated hallux, and AVSD). They found compound heterozygous variants in FUZ [p.(Val209_Leu212del) and p.(Glu201Lys)]. PMID: 29068549 1 fetus with lethal short-rib polydactyly syndrome II-like phenotype and a homozygous variant (c.98_111+9del) in FUZ. 1 individual with asphyxiating thoracic dystrophy (ATD) with polydactyly and a (unclear if homozygous) missense variant [p.(Arg284Leu)] in FUZ. PMID: 34719684 Monozygotic twins with craniosynostosis (1 x metopic, 1 x metopic/coronal) and a homozygous missense variant in FUZ [p.(Arg284Pro)]. They cultured primary osteoblasts and mouse embryonic fibroblasts from Fuz mutant mice. Loss of Fuz resulted in increased osteoblastic mineralisation, suggesting that the FUZ protein normally acts as a negative regulator of osteogenesis. Sources: Literature |
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| Skeletal dysplasia v0.265 | KIAA0586 |
Elena Savva gene: KIAA0586 was added gene: KIAA0586 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: KIAA0586 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0586 were set to PMID: 36538006; 26096313; 26166481 Phenotypes for gene: KIAA0586 were set to Joubert syndrome 23 MIM#616490; Short-rib thoracic dysplasia 14 with polydactyly MIM#616546 Review for gene: KIAA0586 was set to GREEN Added comment: PMID: 36538006 - fetus with post-axial polydactyly, short limbs and persistent left superior vena cava (PLSVC) with a dilated coronary sinus. Chet variants c.3940+1G>A and c.3303G>A (synonymous) were identified. Functional studies support an impact for both variants. PMID: 26096313 - 9 unrelated families with Joubert syndrome. MRI shows the molar tooth sign in 3/3 scanned patients. Patients tended to have biallelic PTCs, though missense also reported. p.Arg143Lysfs*4 appears to be a recurring mutation, seen in patients either as a homozygote or in chet with another unique mutation in 7/9 families. Interestingly these 7 families were of different ethnicity PMID: 26166481 - Four unrelated families reported with a severe neurological/skeletal phenotype. However, note same variant identified in three of the families, indicative of founder effect. Gene is also associated with Joubert syndrome. Sources: Literature |
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| Skeletal dysplasia v0.259 | SOX8 |
Paul De Fazio gene: SOX8 was added gene: SOX8 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: SOX8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SOX8 were set to https://www.neurology.org/doi/full/10.1212/NXG.0000000000200088 Phenotypes for gene: SOX8 were set to Neurodevelopmental disorder (MONDO:0700092), SOX8-related Review for gene: SOX8 was set to RED gene: SOX8 was marked as current diagnostic Added comment: Proband presented to genetics clinic at 27 years of age with BMI -3.4SD, height -2.7SD, head circumference -1.8SD. She had mild intellectual delay and clinical features of a congenital, nonprogressive myopathy with moderate proximal and distal weakness. X-rays showed skeletal dysplasia, including cervical thoracic scoliosis and lumbar scoliosis. She was reported as having had weakness at birth with poor suck, micrognathia, hypotonia, and talipes. She was documented to have significant motor delay as a child. MRI of the brain demonstrated large posterior fossa CSF spaces. Biallelic SOX8 variants biallelic (NM_014587.3:c.422+5G>C; c.583dup p.(His195ProfsTer11)) were identified by WGS. The +5 variant was shown to affect splicing, while the frameshift variant resulted in production of low-level truncated protein (not NMD predicted). Functional studies on patient fibroblasts showed misregulation of downstream SOX8 targets. Sources: Literature |
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| Skeletal dysplasia v0.254 | CSGALNACT1 |
Zornitza Stark gene: CSGALNACT1 was added gene: CSGALNACT1 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: CSGALNACT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CSGALNACT1 were set to 31705726; 31325655 Phenotypes for gene: CSGALNACT1 were set to Skeletal dysplasia, mild, with joint laxity and advanced bone age, MIM# 618870 Review for gene: CSGALNACT1 was set to GREEN Added comment: Four families reported. Sources: Expert Review |
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| Skeletal dysplasia v0.252 | MAB21L2 |
Zornitza Stark gene: MAB21L2 was added gene: MAB21L2 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: MAB21L2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAB21L2 were set to 24906020; 25719200; 31037784; 30375740; 30073347; 26116559 Phenotypes for gene: MAB21L2 were set to Microphthalmia/coloboma and skeletal dysplasia syndrome, MIM# 615877 Review for gene: MAB21L2 was set to GREEN Added comment: More than 7 unrelated families reported with microphthalmia/anophthalmia/coloboma and rhizomelia. Several individuals with the c.151C > T (p.Arg51Cys) variant also had ID. One family reported with eye phenotype and bi-allelic missense variants, LIMITED evidence for bi-allelic disease. Three different animal models support gene-disease association. Sources: Expert Review |
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| Skeletal dysplasia v0.241 | PLK4 |
Zornitza Stark changed review comment from: At least 3 unrelated families reported with autosomal recessive developmental disorder characterised by delayed psychomotor development, visual impairment, and microcephaly.; to: At least 3 unrelated families reported with autosomal recessive developmental disorder characterised by delayed psychomotor development, visual impairment, and microcephaly. Short stature but no specific skeletal abnormalities. |
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| Skeletal dysplasia v0.241 | PHF6 |
Zornitza Stark changed review comment from: Clinical features are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected. More than 20 families reported.; to: Clinical features are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected. More than 20 families reported. Abnormal skeletal features including thickened calvarium and abnormal vertebrae reported. |
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| Skeletal dysplasia v0.238 | IFT74 |
Naomi Baker gene: IFT74 was added gene: IFT74 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: IFT74 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IFT74 were set to PMID:37315079 Phenotypes for gene: IFT74 were set to Jeune syndrome (MONDO:0018770), IFT74-related Review for gene: IFT74 was set to GREEN Added comment: Five individuals from four families reported. A homozygous exon 2 deletion was identified in two families, and splice variants were identified in the other two families (with minigene experiments demonstrating an effect on splicing of the non-canonical/deep intronic splice variants). Authors also characterised three mouse Ift74 alleles, with phenotypes ranging from a severe mid gestational lethal phenotype in the Ift74Tm1d out of frame exon 3 deletion allele, a post-natal lethal phenotype in the Ift74Tm1a exon 2 skip allele, to no detectable phenotype in Ift74Tm1b in frame exon 3 deletion allele. Sources: Literature |
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| Skeletal dysplasia v0.229 | DDRGK1 |
Achchuthan Shanmugasundram gene: DDRGK1 was added gene: DDRGK1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336 Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type, OMIM:602557 Review for gene: DDRGK1 was set to GREEN Added comment: Comment on gene classification: This gene should be rated GREEN as it has been associated with Spondyloepimetaphyseal dysplasia, Shohat type from seven unrelated cases from multiple ethnicities and supported by functional studies. PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development. PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD. In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455). This gene has been associated with relevant phenotype in OMIM (MIM #602557), but not in Gene2Phenotype. Sources: Literature |
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| Skeletal dysplasia v0.227 | CBFB |
Ain Roesley gene: CBFB was added gene: CBFB was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CBFB were set to 36241386 Phenotypes for gene: CBFB were set to cleidocranial dysplasia (MONDO#0007340), CBFB-related Penetrance for gene: CBFB were set to Complete Review for gene: CBFB was set to GREEN gene: CBFB was marked as current diagnostic Added comment: 5 families with 8 individuals, including 2 de novos and 1 intragenic exon 4 deletion In 1 family, the mother did not report skeletal concerns but had dental abnormalities during childhood Sources: Literature |
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| Skeletal dysplasia v0.219 | FAM20B |
Zornitza Stark gene: FAM20B was added gene: FAM20B was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: FAM20B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAM20B were set to 30847897; 30105814; 22732358; 27405802 Phenotypes for gene: FAM20B were set to Desbuquois dysplasia MONDO:0015426 Review for gene: FAM20B was set to AMBER Added comment: Two siblings from a single family with neonatal short limb dysplasia resembling Desbuquois dysplasia. One of the siblings underwent genetic testing and compound heterozygous variants were identified in FAM20B ((NM_014864: c.174_178delTACCT p.T59Afs*19/c.1038delG p.N347Mfs*4). Multiple mouse models reported with skeletal abnormalities. Sources: Literature |
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| Skeletal dysplasia v0.217 | EXOC6B |
Bryony Thompson gene: EXOC6B was added gene: EXOC6B was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: EXOC6B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXOC6B were set to 26669664; 30284759; 36150098 Phenotypes for gene: EXOC6B were set to Spondyloepimetaphyseal dysplasia with joint laxity MONDO:0019675 Review for gene: EXOC6B was set to GREEN Added comment: 6 affected individuals from 4 families, and supporting assays in patient cells PMID: 26669664 - 2 brothers with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones from a consanguineous family, with a homozygous nonsense variant [c.906T>A/p.(Tyr302*)] PMID: 30284759 - 2 sisters with dislocations of the hips and knees, long slender fingers with distal tapering, significant motor disability but normal (older sister) or low-normal intelligence (younger sister), with a homozygous in-frame deletion of exons 9-20 PMID: 36150098 - 2 unrelated probands from consanguineous families, one with a homozygous frameshift exon 20 deletion and one with a homozygous nonsense variant (c.401T>G p.Leu134Ter). Function assessment of patient fibroblast cell lines indicated abrogation of exocytosis leading to impaired primary ciliogenesis Sources: Literature |
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| Skeletal dysplasia v0.209 | ACVR1 |
Zornitza Stark changed review comment from: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Note variants in this gene are also associated with congenital heart disease, PMID 29089047.; to: Fibrodysplasia ossificans progressiva is a rare autosomal dominant disease with complete penetrance involving progressive ossification of skeletal muscle, fascia, tendons, and ligaments. FOP has a prevalence of approximately 1 in 2 million worldwide, and shows no geographic, ethnic, racial, or gender preference. Individuals with FOP appear normal at birth except for great toe abnormalities: the great toes are short, deviated, and monophalangic. Ossification occurs progressively over the course of a lifetime in an inevitable and unpredictable episodic manner. Multiple unrelated families reported. The R206H variant is recurrent. Clinical trial with palovarotene. Note variants in this gene are also associated with congenital heart disease, PMID 29089047. |
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| Skeletal dysplasia v0.205 | MPDU1 |
Zornitza Stark changed review comment from: More than 5 unrelated families reported. Prominent ichthyosis reported in some, in addition to neurological features including DD/ID, seizures, hypotonia. Some reported with features overlapping dystroglycanopathy, including raised CK.; to: More than 5 unrelated families reported. Prominent ichthyosis reported in some, in addition to neurological features including DD/ID, seizures, hypotonia. Some reported with features overlapping dystroglycanopathy, including raised CK. Listed in the skeletal nosology paper as a condition resembling storage diseases, occasional reports of severe short stature. |
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| Skeletal dysplasia v0.180 | GINS3 |
Zornitza Stark gene: GINS3 was added gene: GINS3 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: GINS3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GINS3 were set to 35603789 Phenotypes for gene: GINS3 were set to Meier-Gorlin syndrome, MONDO:0016817, GINS3-related Review for gene: GINS3 was set to GREEN Added comment: 7 individuals from 5 families reported, presenting with prenatal and postnatal growth deficiency as well as other features. Three unique missense variants identified, two affecting p.Asp24. These variants are thought to be hypomorphic. Supportive mouse model. Sources: Literature |
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| Skeletal dysplasia v0.175 | MECOM |
chirag patel gene: MECOM was added gene: MECOM was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MECOM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MECOM were set to PMID: 35219593, 26581901, 29519864 Phenotypes for gene: MECOM were set to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2, OMIM # 616738; Radioulnar synostosis without hematological aberration, no OMIM # Review for gene: MECOM was set to GREEN Added comment: Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 -Multiple affected families reported Radioulnar synostosis (RUS) without hematological aberration -8 families with RUS and no identifiable hematological abnormalities -WES identified unique missense variants in MECOM -6 families had variants in residue R781, 2 other variants included I783T and Q777E. All variants clustered within the ninth zinc finger motif of EVI1. -Functional experiments showed that MECOM R781C led to alterations in TGF-β–mediated transcriptional responses. Sources: Literature |
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| Skeletal dysplasia v0.153 | SEMA3A |
Krithika Murali gene: SEMA3A was added gene: SEMA3A was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827 Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; short stature Review for gene: SEMA3A was set to GREEN Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). More severe phenotype with biallelic SEMA3A variants reported including postnatal short stature and congenital heart defects in 3/3 published, unrelated individuals. PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia. PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth) PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly Sources: Literature |
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| Skeletal dysplasia v0.152 | ARSK |
Paul De Fazio gene: ARSK was added gene: ARSK was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARSK were set to 34916232; 32856704 Phenotypes for gene: ARSK were set to Mucopolysaccharidosis MONDO:0019249, ARSK-related Review for gene: ARSK was set to GREEN gene: ARSK was marked as current diagnostic Added comment: 4 individuals from 2 unrelated consanguineous families reported with a homozygous missense and an NMD-predicted nonsense variant, who had features of mucopolysaccharidosis such as short stature, coarse facial features and dysostosis multiplex. Urinary GAG excretion was normal by conventional methods, but LC-MS/MS in 2 individuals revealed an increase in specific dermatan sulfate-derived disaccharides. Functional studies showed reduced protein levels and reduced enzyme activity for the nonsense and missense variant respectively. A mouse model also shows a mucopolysaccharidosis phenotype, albeit milder. Rated green (2 families, functional evidence, mouse model). Sources: Literature |
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| Skeletal dysplasia v0.150 | SMAD6 |
Chris Richmond gene: SMAD6 was added gene: SMAD6 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD6 were set to 31138930 Phenotypes for gene: SMAD6 were set to 179300 Penetrance for gene: SMAD6 were set to Incomplete Review for gene: SMAD6 was set to GREEN gene: SMAD6 was marked as current diagnostic Added comment: Yang et al. (2019) performed exome sequencing on 117 patients with sporadic RUS and found significant enrichment for loss-of-function variants in the SMAD6 gene. Identified 22 SMAD6 rare variants (with a minor allele frequency of less than 0.0001) that occurred in 22 nonsyndromic RUS patients. Logistic regression showed that SMAD6 loss-of-function variants were significantly associated with increased risk of nonsyndromic RUS (OR 430; 95% CI 237.5-780.1; p less than 0.000001). Some inherited from unaffected parents. Sources: Expert Review |
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| Skeletal dysplasia v0.140 | HHAT | Zornitza Stark edited their review of gene: HHAT: Added comment: Additional family reported, with severe microcephaly, skeletal dysplasia and sex reversal phenotype.; Changed rating: GREEN; Changed publications: 24784881, 30912300, 33749989; Changed phenotypes: Nivelon-Nivelon-Mabille syndrome 600092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.138 | PRKG2 | Zornitza Stark edited their review of gene: PRKG2: Added comment: PMID 34782440: 4 further families reported.; Changed publications: 33106379, 34782440 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.133 | SIK3 |
Krithika Murali gene: SIK3 was added gene: SIK3 was added to Skeletal dysplasia. Sources: Expert list,Literature Mode of inheritance for gene: SIK3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SIK3 were set to 30232230; 22318228 Phenotypes for gene: SIK3 were set to ?Spondyloepimetaphyseal dysplasia, Krakow type - #618162 Review for gene: SIK3 was set to AMBER Added comment: Biallelic SIK3 variants reported in 2 siblings from a consanguineous family with an uncharacterised skeletal dysplasia. Radiographic features included widened/flared metaphyses with irregular ossifications, motheaten long bones, fragmentation of the proximal metacarpals, rounded vertebral bodies, and a distinctive transverse gap seen in the tibias. In addition to the skeletal phenotype, the siblings manifested significant developmental delay with brain MRI abnormalities, a severe unclassified immunodeficiency, and normal parathyroid hormone concentration with mild hypercalcemia. One sibling had a more severe phenotype, particularly immunodeficiency, and died of Epstein-Barr virus induced small muscle cancer at 10 years of age. Mouse models support impaired chondrocyte development with skeletal dysplasia phenotype. Sources: Expert list, Literature |
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| Skeletal dysplasia v0.131 | STT3A |
Elena Savva gene: STT3A was added gene: STT3A was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: STT3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STT3A were set to PMID: 34653363; 23842455; 30701557; 28424003 Phenotypes for gene: STT3A were set to Congenital disorder of glycosylation, type Iw MIM#615596 Mode of pathogenicity for gene: STT3A was set to Other Review for gene: STT3A was set to GREEN Added comment: ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A) PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16). Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged). Sources: Literature |
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| Skeletal dysplasia v0.122 | LRRK1 |
Zornitza Stark gene: LRRK1 was added gene: LRRK1 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: LRRK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRRK1 were set to 27829680; 27055475; 31571209; 32119750 Phenotypes for gene: LRRK1 were set to Osteosclerotic metaphyseal dysplasia (OSMD) (OMIM: 615198) Review for gene: LRRK1 was set to GREEN Added comment: At least 4 unrelated families reported. Sources: Expert Review |
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| Skeletal dysplasia v0.119 | ARID1B | Bryony Thompson changed review comment from: Skeletal limb anomalies, spinal anomalies, and short stature have been reported as a feature of the condition. >3 cases reported.; to: Skeletal limb anomalies, spinal anomalies, and short stature have been reported as a feature of the condition. >3 cases reported, at least one case identified in a skeletal dysplasia cohort. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.118 | ARID1B | Bryony Thompson changed review comment from: Skeletal limb anomalies, spinal anomalies, and short stature have been reported as a feature of the condition. > cases reported.; to: Skeletal limb anomalies, spinal anomalies, and short stature have been reported as a feature of the condition. >3 cases reported. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.115 | ARID1A | Bryony Thompson changed review comment from: At least 5 cases have been reported with skeletal anomalies as a feature of the condition. Mosaicism is very common for the gene.; to: At least 5 cases have been reported with skeletal anomalies (brachydactyly and polydactyly) as a feature of the condition. Mosaicism is very common for the gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.104 | LAMA5 |
Bryony Thompson gene: LAMA5 was added gene: LAMA5 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: LAMA5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LAMA5 were set to 33242826 Phenotypes for gene: LAMA5 were set to Bent bone dysplasia Review for gene: LAMA5 was set to RED Added comment: A single family with 3 affected siblings with biallelic variants, and some supporting in vitro functional assays. Sources: Literature |
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| Skeletal dysplasia v0.91 | CHST11 |
Zornitza Stark gene: CHST11 was added gene: CHST11 was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: CHST11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CHST11 were set to 26436107; 29514872 Phenotypes for gene: CHST11 were set to Osteochondrodysplasia, brachydactyly, and overlapping malformed digits, MIM# 618167 Review for gene: CHST11 was set to AMBER Added comment: Two unrelated families reported, note one had a homozygous deletion. Sources: Expert list |
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| Skeletal dysplasia v0.89 | MIA3 |
Zornitza Stark gene: MIA3 was added gene: MIA3 was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MIA3 were set to 32101163; 33778321 Phenotypes for gene: MIA3 were set to Ondontochondrodysplasia 2 with hearing loss and diabetes , MIM#619269 Review for gene: MIA3 was set to AMBER Added comment: Odontochondrodysplasia-2 with hearing loss and diabetes (ODCD2) is characterized by growth retardation with proportionate short stature, dentinogenesis imperfecta, sensorineural hearing loss, insulin-dependent diabetes, and mild intellectual disability. Four affected siblings reported, homozygous variant affecting splicing. Mouse model has absence of bone mineralization. Sources: Expert list |
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| Skeletal dysplasia v0.85 | DONSON |
Zornitza Stark gene: DONSON was added gene: DONSON was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: DONSON was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DONSON were set to 28191891; 28630177; 28191891 Phenotypes for gene: DONSON were set to Microcephaly, short stature, and limb abnormalities, MIM# 617604; Microcephaly-micromelia syndrome, MIM# 251230 Review for gene: DONSON was set to GREEN Added comment: MISSLA, MIM# 617604 is an autosomal recessive disorder characterized by intrauterine growth retardation, microcephaly (-2.4 to -10.7 SD), variable short stature (-1.2 SD to -4 SD, although 1 individual had stature of -8.4 SD), and limb abnormalities mainly affecting the upper limb and radial ray. Affected individuals typically have mild intellectual disability, but may have normal development. At least 20 unrelated families reported. Microcephaly-micromelia syndrome (MIM#251230), is a more severe disorder that usually results in intrauterine or perinatal death. Multiple affected individuals reported with homozygous c.1047-9A-G variant, from different ethnicities. Sources: Expert Review |
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| Skeletal dysplasia v0.83 | EN1 |
Zornitza Stark changed review comment from: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype. Sources: Literature; to: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype. An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant. Sources: Literature |
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| Skeletal dysplasia v0.82 | EN1 |
Zornitza Stark gene: EN1 was added gene: EN1 was added to Skeletal dysplasia. Sources: Literature SV/CNV, 5'UTR tags were added to gene: EN1. Mode of inheritance for gene: EN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EN1 were set to 33568816 Phenotypes for gene: EN1 were set to ENDOVE syndrome, limb-only type, MIM# 619217 Review for gene: EN1 was set to GREEN Added comment: Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some. Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene. Mouse model recapitulated the phenotype. Sources: Literature |
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| Skeletal dysplasia v0.71 | SCUBE3 |
Zornitza Stark gene: SCUBE3 was added gene: SCUBE3 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: SCUBE3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCUBE3 were set to 33308444 Phenotypes for gene: SCUBE3 were set to Short stature; skeletal abnormalities; craniofacial abnormalities; dental anomalies Review for gene: SCUBE3 was set to GREEN Added comment: Eighteen affected individuals from nine unrelated families reported with a consistent phenotype characterised by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. Mouse model recapitulated phenotype. Sources: Literature |
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| Skeletal dysplasia v0.70 | FBLN1 |
Zornitza Stark changed review comment from: Single association to disease published in literature - reciprocal translocation region t(12;22)(p11.2;q13.3) found in the family. The breakpoint was located in the intron between the last 2 exons of the FBLN1-D splice variant isoform (exons 19-20). Additional pathogenic missense in ClinVar, but a research finding and inherited; to: Single association of mono-allelic variants to disease published in literature - reciprocal translocation region t(12;22)(p11.2;q13.3) found in the family. The breakpoint was located in the intron between the last 2 exons of the FBLN1-D splice variant isoform (exons 19-20). Additional pathogenic missense in ClinVar, but a research finding and inherited. Single report of homozygous missense in a family with syndactyly, undescended testes, delayed motor milestones, mental retardation and signs of brain atrophy. |
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| Skeletal dysplasia v0.67 | HHAT |
Zornitza Stark gene: HHAT was added gene: HHAT was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HHAT were set to 24784881; 30912300 Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092 Review for gene: HHAT was set to AMBER Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia. Sources: Expert list |
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| Skeletal dysplasia v0.65 | TONSL |
Zornitza Stark gene: TONSL was added gene: TONSL was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: TONSL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TONSL were set to 30773277; 30773278; 32959051 Phenotypes for gene: TONSL were set to Spondyloepimetaphyseal dysplasia, sponastrime type OMIM:271510; spondyloepimetaphyseal dysplasia, sponastrime type MONDO:0010068 Review for gene: TONSL was set to GREEN Added comment: Associated with Spondyloepimetaphyseal dysplasia, sponastrime type MIM#271510 (AR) in OMIM. PMID: 30773277 - Burrage et al 2019 - identified, using WES or Sanger sequencing, compound heterozygous variants in TONSL in 9 individuals (8 families) with SPONASTRIME dysplasia. 4 other probands with SPONASTRIME dysplasia did not have biallelic variants in TONSL or in MMS22L, but two of them did have a single heterozygous variants in TONSL. The authors say they cannot exclude deep intronic, promotor variants or large intragenic rearrangements/deletions in these patients. An additional 4 individuals (3 families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities were also found to have compound heterozygous variants in TONSL. PMID: 30773278 - Chang et al 2019 - Using WES they identified homozygous or compound heterozygous TONSL variants in 10 of 13 individuals (9 families) with SPONASTRIME dysplasia. PMID: 32959051 - Micale et al 2020 - report a 9-year-old Italian girl with typical SPONASTRIME dysplasia who was found to have two novel missense variants in TONSL. Each parent was heterozygous for one of the variants. Both variants were found to be very rare in the gnomad database. Patient-derived fibroblasts show increased levels of spontaneous chromosomal breaks, reduced cell proliferation and enhanced apoptosis. Sources: Literature |
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| Skeletal dysplasia v0.55 | WDPCP | Zornitza Stark changed review comment from: Two families reported; the first one with a BBS phenotype, and in the second one affected individual had polysyndactyly and tongue hamartomas, so phenotype consistent with OFD rather than BBS.; to: Four families reported with ciliopathy phenotypes, including BBS, OFD, syndromic retinopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.47 | MBTPS1 |
Zornitza Stark gene: MBTPS1 was added gene: MBTPS1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013 Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia Review for gene: MBTPS1 was set to GREEN Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature. Sources: Literature |
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| Skeletal dysplasia v0.45 | MTX2 |
Zornitza Stark gene: MTX2 was added gene: MTX2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTX2 were set to 32917887 Phenotypes for gene: MTX2 were set to Mandibuloacral dysplasia; lipodystrophy; arterial calcification Review for gene: MTX2 was set to GREEN Added comment: Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature |
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| Skeletal dysplasia v0.38 | GNPNAT1 |
Zornitza Stark gene: GNPNAT1 was added gene: GNPNAT1 was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GNPNAT1 were set to 32591345 Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia Review for gene: GNPNAT1 was set to AMBER Added comment: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype. Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1. Sources: Expert list |
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| Skeletal dysplasia v0.37 | PLCB3 |
Zornitza Stark gene: PLCB3 was added gene: PLCB3 was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: PLCB3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLCB3 were set to 29122926 Phenotypes for gene: PLCB3 were set to Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961 Review for gene: PLCB3 was set to RED Added comment: Single consanguineous family reported. Sources: Expert list |
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| Skeletal dysplasia v0.29 | COG4 |
chirag patel changed review comment from: Saul-Wilson syndrome (AD) 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg) Congenital disorder of glycosylation, type IIj (AR) Sources: Literature; to: Saul-Wilson syndrome (AD) 14 patients reported with DD, skeletal dysplasia changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg) Congenital disorder of glycosylation, type IIj (AR) Sources: Literature |
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| Skeletal dysplasia v0.29 | COG4 |
chirag patel gene: COG4 was added gene: COG4 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: COG4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: COG4 were set to PMID: 31949312; 30290151 Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM #618150; Congenital disorder of glycosylation, type IIj, OMIM #613489 Review for gene: COG4 was set to GREEN Added comment: Saul-Wilson syndrome (AD) 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg) Congenital disorder of glycosylation, type IIj (AR) Sources: Literature |
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| Skeletal dysplasia v0.14 | PKDCC |
Zornitza Stark gene: PKDCC was added gene: PKDCC was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PKDCC were set to 30478137; 19097194 Phenotypes for gene: PKDCC were set to Rhizomelia; dysmorphism Review for gene: PKDCC was set to AMBER Added comment: Two unrelated consanguineous families reported with different homozygous variants Pre-existing mouse model has similar phenotype Sources: Literature |
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| Skeletal dysplasia v0.11 | MIR140 |
Chris Richmond gene: MIR140 was added gene: MIR140 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: MIR140 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MIR140 were set to 30804514; 31633310 Phenotypes for gene: MIR140 were set to 618618 Penetrance for gene: MIR140 were set to unknown Mode of pathogenicity for gene: MIR140 was set to Other Review for gene: MIR140 was set to GREEN Added comment: Single clinical paper (30804514) reports variant in affected mother and child (de novo in mother) and in a separate unrelated female (de novo) with spondylo-epiphyseal dysplasia. Mouse model (21576357) deletion of gene causes impaired longitudinal bone growth. Separate mouse model studies by same authors as clinical paper above (30804514) showed phenotype of mice with same mutation in this gene consistent with the skeletal dysplasia features of patients with the n.24A-G mutation, suggestive of neomorphic effects (mutation produces both loss-of-function and gain-of-function effects.) Sources: Expert Review |
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| Skeletal dysplasia v0.9 | RSPRY1 |
Zornitza Stark gene: RSPRY1 was added gene: RSPRY1 was added to Skeletal dysplasia. Sources: Expert list Mode of inheritance for gene: RSPRY1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RSPRY1 were set to 26365341 Phenotypes for gene: RSPRY1 were set to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 Review for gene: RSPRY1 was set to AMBER Added comment: Two unrelated individuals reported, some functional evidence. Sources: Expert list |
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| Skeletal dysplasia v0.4 | MESD |
Zornitza Stark gene: MESD was added gene: MESD was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MESD were set to 31564437 Phenotypes for gene: MESD were set to Osteogenesis imperfecta, type XX, MIM# 618644 Review for gene: MESD was set to GREEN Added comment: Five unrelated families reported. Sources: Other |
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| Skeletal dysplasia v0.1 | PISD |
Zornitza Stark gene: PISD was added gene: PISD was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PISD were set to 30488656; 31263216; 30858161 Phenotypes for gene: PISD were set to Spondylometaphyseal dysplasia with large epiphyses Review for gene: PISD was set to AMBER Added comment: Two unrelated probands from non-consanguineous families identified as having the same homozygous variant; some functional data. Note there was some regions of homozygosity identified, indicative of distant relatedness and therefore founder effect. Three other families reported with bi-allelic variants in this gene in 2019 and a multi-system disorder including short stature, but skeletal findings not as well characterised as in this paper. Sources: Literature |
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| Skeletal dysplasia v0.0 | TOPORS |
Zornitza Stark gene: TOPORS was added gene: TOPORS was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory Mode of inheritance for gene: TOPORS was set to |
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| Skeletal dysplasia v0.0 | PIR |
Zornitza Stark gene: PIR was added gene: PIR was added to Skeletal dysplasia. Sources: Expert Review Red Mode of inheritance for gene: PIR was set to Unknown Publications for gene: PIR were set to 16183656; 19766747 Phenotypes for gene: PIR were set to Osteoporosis |
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| Skeletal dysplasia v0.0 | HDAC5 |
Zornitza Stark gene: HDAC5 was added gene: HDAC5 was added to Skeletal dysplasia. Sources: Expert Review Red,Expert list Mode of inheritance for gene: HDAC5 was set to Unknown Publications for gene: HDAC5 were set to 26723575 Phenotypes for gene: HDAC5 were set to osteoporosis |
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| Skeletal dysplasia v0.0 | FGF8 |
Zornitza Stark gene: FGF8 was added gene: FGF8 was added to Skeletal dysplasia. Sources: Expert Review Red Mode of inheritance for gene: FGF8 was set to Unknown Publications for gene: FGF8 were set to 24569166 Phenotypes for gene: FGF8 were set to Numerous variants reported in Hypogonadotropic hypogonadism 6 with or without anosmia 612702, but this phenotype is not relevant to this panel. |
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| Skeletal dysplasia v0.0 | WNT1 |
Zornitza Stark gene: WNT1 was added gene: WNT1 was added to Skeletal dysplasia. Sources: NHS GMS,Radboud University Medical Center, Nijmegen,Expert,Expert Review Green Mode of inheritance for gene: WNT1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Phenotypes for gene: WNT1 were set to OI/osteoporosis; osteogenesis imperfecta; Osteogenesis imperfecta, type XV, 615220; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221 |
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| Skeletal dysplasia v0.0 | SLC35C1 |
Zornitza Stark gene: SLC35C1 was added gene: SLC35C1 was added to Skeletal dysplasia. Sources: Other,Expert Review Green Mode of inheritance for gene: SLC35C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35C1 were set to 12476046; 11326280 Phenotypes for gene: SLC35C1 were set to GDP-fucose transporter deficiency (Disorders of multiple glycosylation and other glycosylation pathways); Congenital disorder of glycosylation, type IIc 266265 |
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| Skeletal dysplasia v0.0 | SLC34A1 |
Zornitza Stark gene: SLC34A1 was added gene: SLC34A1 was added to Skeletal dysplasia. Sources: Other,Expert Review Green Mode of inheritance for gene: SLC34A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SLC34A1 were set to 12324554; 25050900; 9560283 Phenotypes for gene: SLC34A1 were set to Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286 |
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| Skeletal dysplasia v0.0 | SERPINF1 |
Zornitza Stark gene: SERPINF1 was added gene: SERPINF1 was added to Skeletal dysplasia. Sources: NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,Expert,Illumina TruGenome Clinical Sequencing Services Mode of inheritance for gene: SERPINF1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SERPINF1 were set to OI/osteoporosis; osteogenesis imperfecta; Osteogenesis Imperfecta, Recessive; Osteogenesis imperfecta, type VI, 613982 |
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| Skeletal dysplasia v0.0 | POR |
Zornitza Stark gene: POR was added gene: POR was added to Skeletal dysplasia. Sources: Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,UKGTN,Illumina TruGenome Clinical Sequencing Services Mode of inheritance for gene: POR was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: POR were set to Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571 |
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| Skeletal dysplasia v0.0 | PLS3 |
Zornitza Stark gene: PLS3 was added gene: PLS3 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review,Expert Review Green Mode of inheritance for gene: PLS3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis 300910 |
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| Skeletal dysplasia v0.0 | MATN3 |
Zornitza Stark gene: MATN3 was added gene: MATN3 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,Illumina TruGenome Clinical Sequencing Services Mode of inheritance for gene: MATN3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MATN3 were set to 16199550; 16287128; 15121775; 30080953; 11479597 Phenotypes for gene: MATN3 were set to MED; Multiple Epiphyseal Dysplasia, Dominant; Disproportionate Short Stature; Spondyloepimetaphyseal dysplasia, 608728; Epiphyseal dysplasia, multiple, 5, 607078; {Osteoarthritis susceptibility 2}, 140600; multiple epiphyseal dysplasia |
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| Skeletal dysplasia v0.0 | LRP5 |
Zornitza Stark gene: LRP5 was added gene: LRP5 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Expert,Expert Review Green Mode of inheritance for gene: LRP5 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Phenotypes for gene: LRP5 were set to Exudative vitreoretinopathy 4 601813; Osteoporosis-pseudoglioma syndrome 259770; [Bone mineral density variability 1] 601884; {Osteoporosis} 166710; van Buchem disease, type 2 607636; Osteopetrosis, autosomal dominant 1 607634; Hyperostosis, endosteal 144750; Osteosclerosis 144750 |
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| Skeletal dysplasia v0.0 | GHR |
Zornitza Stark gene: GHR was added gene: GHR was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: GHR were set to increased responsiveness to growth hormone 604271; {Hypercholesterolemia, familial, modification of}, 143890; Short stature, 604271; Proportionate Short Stature/Small for Gestational Age; Growth hormone insensitivity; Increased responsiveness to growth hormone; Laron dwarfism, 262500 |
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| Skeletal dysplasia v0.0 | DDR2 |
Zornitza Stark gene: DDR2 was added gene: DDR2 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green Mode of inheritance for gene: DDR2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DDR2 were set to Spondylometaepiphyseal dysplasia, short limb-hand type 271665; Spondylometaepiphyseal dysplasia, short limb-hand type 271665, at least 3 cases reported |
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| Skeletal dysplasia v0.0 | ANO5 |
Zornitza Stark gene: ANO5 was added gene: ANO5 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Expert Review Green Mode of inheritance for gene: ANO5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ANO5 were set to Disproportionate Short Stature; Osteogenesis Imperfecta and Decreased Bone Density; Gnatodiaphyseal dysplasia; skeletal dysplasias |
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