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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
Skeletal dysplasia v0.425 KIF22 Zornitza Stark Phenotypes for gene: KIF22 were changed from Spondyloepimetaphyseal dysplasia with joint laxity, type 2 603546 to Spondyloepimetaphyseal dysplasia with joint laxity, type 2, MIM# 603546
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
Skeletal dysplasia v0.418 KYNU Chirag Patel gene: KYNU was added
gene: KYNU was added to Skeletal dysplasia. Sources: Expert Review Green,NHS GMS,Victorian Clinical Genetics Services
Mode of inheritance for gene: KYNU was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KYNU were set to 17334708; 28792876; 31923704
Phenotypes for gene: KYNU were set to Hydroxykynureninuria MIM#236800; Vertebral, cardiac, renal, and limb defects syndrome 2 MIM#617661; Disorders of histidine, tryptophan or lysine metabolism
Skeletal dysplasia v0.377 KIF24 Chirag Patel gene: KIF24 was added
gene: KIF24 was added to Skeletal dysplasia. Sources: Genomics England PanelApp
Mode of inheritance for gene: KIF24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF24 were set to 35748595
Phenotypes for gene: KIF24 were set to Skeletal dysplasia MONDO:0018230, KIF24 related
Review for gene: KIF24 was set to GREEN
Added comment: 6 individuals from 3 unrelated families affected by a spectrum of skeletal abnormalities ranging from a lethal fetal skeletal ciliopathy to acromesomelic skeletal dysplasia and a less severe spondylometaphyseal dysplasia. All individuals had different biallelic missense variants in KIF24 which segregated with the phenotype. In vitro studies showed that ciliogenesis and cytokinesis were severely affected in amnioblasts of one affected fetus.
Sources: Genomics England PanelApp
Skeletal dysplasia v0.367 RSPRY1 Zornitza Stark commented on gene: RSPRY1: PMIDs 30063090, 38562122 and 39940902 add three additional unrelated families (total 5 families, 12 patients) with autosomal recessive loss‑of‑function RSPRY1 variants causing spondyloepimetaphyseal dysplasia, Faden‑Alkuraya type.
Skeletal dysplasia v0.367 MET Zornitza Stark Marked gene: MET as ready
Skeletal dysplasia v0.367 MET Zornitza Stark Gene: met has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v0.367 MET Zornitza Stark Classified gene: MET as Amber List (moderate evidence)
Skeletal dysplasia v0.367 MET Zornitza Stark Gene: met has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v0.366 MET Zornitza Stark gene: MET was added
gene: MET was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MET was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MET were set to 26637977
Phenotypes for gene: MET were set to {Osteofibrous dysplasia, susceptibility to} 607278
Review for gene: MET was set to AMBER
Added comment: OSFD is characterized by radiolucent lesions located at the periosteal surface of the diaphyseal cortex, almost exclusively of the tibia and fibula. These lesions are congenital and spontaneously resolve during skeletal maturation.

Three germline variants and one ?somatic variant identified in PMID 26637977, all abolished the splice inclusion of exon 14 in MET transcripts, which resulted in a MET receptor (MET(Δ14)) lacking a cytoplasmic juxtamembrane domain. Incomplete penetrance.
Sources: Literature
Skeletal dysplasia v0.363 RSPRY1 Zornitza Stark Phenotypes for gene: RSPRY1 were changed from Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, 616585 to Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, MIM# 616723
Skeletal dysplasia v0.362 RSPRY1 Zornitza Stark edited their review of gene: RSPRY1: Changed phenotypes: Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type, MIM# 616723
Skeletal dysplasia v0.339 MIA3 Zornitza Stark edited their review of gene: MIA3: Added comment: Upgrade to Green Two additional unrelated individuals from consanguineous families with biallelic variants. Affected individuals presented with short stature, metaphyseal dysplasia, dentinogenesis imperfecta, dental anomalies, and hearing loss.; Changed publications: 32101163, 33778321, 40948380, 40119123
Skeletal dysplasia v0.337 PTBP1 Lucy Spencer gene: PTBP1 was added
gene: PTBP1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PTBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTBP1 were set to 40965981
Phenotypes for gene: PTBP1 were set to Neurodevelopmental disorder (MONDO:0700092), PTBP1-related
Review for gene: PTBP1 was set to GREEN
Added comment: PMID: 40965981 27 individuals with abnormal prenatal ultrasound in thirteen (48%) including short femora, IUGR, hydramnios, increased nuchal translucency, asymmetry of heart cavities, and bilateral hydronephrosis. Skeletal anomalies were seen in 24 (89%), short stature/limbs in 63%, facial dysmorphism 25 (93%), developmental delay in 78%, behavioral problems in 30% and ID in 26% generally mild/moderate, 43% had variable brain MRI abnormalities. additional features included skin, nail, and hair anomalies (52%), dental anomalies (37%), ophthalmological findings (44%), and cardiovascular defects (22%).

Variants a mix of missense and startloss, and were confirmed de novo in 23/17 cases.

Various functional studies showed reduced nuclear localization and enhanced cytoplasmic retention, with start-loss variants also leading to increased protein stability.
Sources: Literature
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
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
Skeletal dysplasia v0.308 XYLT1_DBQD2_GGC Bryony Thompson STR: XYLT1_DBQD2_GGC was added
STR: XYLT1_DBQD2_GGC was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for STR: XYLT1_DBQD2_GGC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: XYLT1_DBQD2_GGC were set to 30554721
Phenotypes for STR: XYLT1_DBQD2_GGC were set to Desbuquois dysplasia 2 MIM#615777
Review for STR: XYLT1_DBQD2_GGC was set to GREEN
STR: XYLT1_DBQD2_GGC was marked as clinically relevant
STR: XYLT1_DBQD2_GGC was marked as current diagnostic
Added comment: 10 patients from 8 families with homozygosity or compound heterozygosity for a (GGC)n repeat expansion in the XYLT1 promoter region, resulting in hypermethylation of XYLT1 exon 1. The GGC repeat region contains (GGC)n-AGC-(GGC)n-(GGA)n. Other loss of function variants in this gene also cause disease.
Normal: 9-20 GGC repeats
Pathogenic: 120-800 repeats
Sources: Literature
Skeletal dysplasia v0.302 PAPSS2 Zornitza Stark Phenotypes for gene: PAPSS2 were changed from Brachyolmia 4 with mild epiphyseal and metaphyseal changes 612847 to Brachyolmia 4 with mild epiphyseal and metaphyseal changes MIM#612847
Skeletal dysplasia v0.296 CTGF Bryony Thompson Phenotypes for gene: CTGF were changed from Kyphomelic dysplasia to Kyphomelic dysplasia MONDO:0008881; Spondyloepimetaphyseal dysplasia MONDO:0100510
Skeletal dysplasia v0.294 CTGF Bryony Thompson reviewed gene: CTGF: Rating: RED; Mode of pathogenicity: None; Publications: 39414788, 20534727; Phenotypes: Spondyloepimetaphyseal dysplasia MONDO:0100510; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v0.289 DDX41 Chirag Patel gene: DDX41 was added
gene: DDX41 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: DDX41 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX41 were set to PMID: 39453476
Phenotypes for gene: DDX41 were set to Bone dysplasia, ichthyosis, and dysmorphism
Review for gene: DDX41 was set to RED
Added comment: 1 patient with acromesomelic dysplasia (short stature, premature closure of epiphyses of hands/feet), chronic ichthyotic-like skin changes, joint pain, facial dysmorphism, dental crowding, difficulty in swallowing, hyperinsulinism, and absent breast development.. WES identified compound heterozygous DDX41 variants (p.Met155Ile and p.Glu345Lys). Parents confirmed carriers of single variant.

DDX41 (DEAD‑box helicase 41) is a member of the largest family of RNA helicases. The DEAD-box RNA helicases regulate all aspects of RNA metabolism. DDX41 acts as a sensor of viral DNA and activates the STING-TBK1-IRF3-type I IFN signaling pathway. Functional analyses of the patient-derived dermal fibroblasts revealed a reduced abundance of DDX41 and abrogated activation of the IFN genes through the STING-type I interferon pathway. Genome-wide transcriptome analyses in the patient's fibroblasts revealed significant gene dysregulation and changes in the RNA splicing events. The patient's fibroblasts also displayed upregulation of periostin mRNA expression. Using an RNA binding protein assay, they identified DDX41 as a novel regulator of periostin expression.
Sources: Literature
Skeletal dysplasia v0.280 PISD Zornitza Stark Phenotypes for gene: PISD were changed from Liberfarb syndrome MIM# 618889; Spondylometaphyseal dysplasia with large epiphyses to Liberfarb syndrome MIM# 618889; Spondylometaphyseal dysplasia with large epiphyses, MONDO:0100510
Skeletal dysplasia v0.279 PISD Zornitza Stark Phenotypes for gene: PISD were changed from Spondylometaphyseal dysplasia with large epiphyses to Liberfarb syndrome MIM# 618889; Spondylometaphyseal dysplasia with large epiphyses
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
Skeletal dysplasia v0.272 UFSP2 Chern Lim reviewed gene: UFSP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 37214758; Phenotypes: Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Skeletal dysplasia v0.259 ERI1 Zornitza Stark Phenotypes for gene: ERI1 were changed from Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related to Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663
Skeletal dysplasia v0.258 ERI1 Zornitza Stark reviewed gene: ERI1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spondyloepimetaphyseal dysplasia, Guo-Salian type, MIM# 620663; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.256 AXIN1 Zornitza Stark Phenotypes for gene: AXIN1 were changed from Syndromic disease, (MONDO:0002254), AXIN1-related to Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558
Skeletal dysplasia v0.255 AXIN1 Zornitza Stark reviewed gene: AXIN1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Craniometadiaphyseal osteosclerosis with hip dysplasia, MIM# 620558; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.237 ERI1 Elena Savva Phenotypes for gene: ERI1 were changed from Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related
Skeletal dysplasia v0.234 ERI1 Elena Savva gene: ERI1 was added
gene: ERI1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to Spondyloepimetaphyseal dysplasia (MONDO#0100510), ERI1-related, Intellectual disability (MONDO#0001071), ERI1-related
Review for gene: ERI1 was set to GREEN
Added comment: PMID: 37352860 - 8 individuals from 7 unrelated families
- Patients with biallelic missense show a MORE severe spondyloepimetaphyseal dysplasia, syndactyly, brachydactyly/clinodactyly/camptodactyly
- Patients with biallelic null/whole gene deletion had mild ID and digit anomalies including brachydactyly/clinodactyly/camptodactyly
- Patient chet for a missense and PTC variant has a blended phenotype with short stature, syndactyly, brachydactyly/clinodactyly/camptodactyly, mild ID and failure to thrive

- Missense variants were functionally shown to not be able to rescue 5.8S rRNA processing in KO HeLa cells
- K/O mice had neonatal lethality with growth defects, brachydactyly. Skeletal-specific K/O had mild platyspondyly, had more in keeping with patients with null variants than missense

More severe phenotype hypothesised due to "exonuclease-dead proteins may compete for the target RNA molecules with other exonucleases that have functional redundancy
with ERI1, staying bound to those RNA molecules"
Sources: Literature
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
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
Skeletal dysplasia v0.212 SLC13A1 Lucy Spencer gene: SLC13A1 was added
gene: SLC13A1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: SLC13A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A1 were set to 36175384
Phenotypes for gene: SLC13A1 were set to sulfation-related bone disorder MONDO:0019688, SLC13A1-related
Review for gene: SLC13A1 was set to RED
Added comment: PMID: 36175384- 1 patient with a homozygous nonsense variant in SLC13A1. Patient has enlargements of the joints, and spondylo-epi-metaphyseal radiological abnormalities in early childhood, which improved with age. Also autistic features and hyposulfatemia and hypersulfaturia, and reduced serum cholesterol sulfate. However the variant in this individual (Arg12Ter) has 569 hets and 1 hom in gnomad.

Also this patient was homozygous for CFTR Ala455Gly which is a known pathogenic variant associated with a less severe CF phenotype.
Sources: Literature
Skeletal dysplasia v0.163 SFRP4 Zornitza Stark Phenotypes for gene: SFRP4 were changed from PYL; Pyle disease 265900; Metaphyseal dysplasia to Pyle disease, MIM#265900
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
Skeletal dysplasia v0.150 GPX4 Zornitza Stark Phenotypes for gene: GPX4 were changed from Spondylometaphyseal dysplasia, Sedaghatian type 250220 to Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220
Skeletal dysplasia v0.147 GPX4 Ain Roesley reviewed gene: GPX4: Rating: GREEN; Mode of pathogenicity: None; Publications: 24706940, 32827718; Phenotypes: Spondylometaphyseal dysplasia, Sedaghatian type MIM#250220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v0.140 PRKG2 Zornitza Stark Phenotypes for gene: PRKG2 were changed from Acromesomelic dysplasia to Acromesomelic dysplasia 4, MIM# 619636; Spondylometaphyseal dysplasia, Pagnamenta type, MIM# 619638
Skeletal dysplasia v0.139 PRKG2 Zornitza Stark edited their review of gene: PRKG2: Changed phenotypes: Acromesomelic dysplasia 4, MIM# 619636, Spondylometaphyseal dysplasia, Pagnamenta type, MIM# 619638
Skeletal dysplasia v0.135 SIK3 Zornitza Stark Phenotypes for gene: SIK3 were changed from ?Spondyloepimetaphyseal dysplasia, Krakow type - #618162 to Spondyloepimetaphyseal dysplasia, Krakow type - #618162
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
Skeletal dysplasia v0.129 BGN Krithika Murali gene: BGN was added
gene: BGN was added to Skeletal dysplasia. Sources: Expert list,Literature
Mode of inheritance for gene: BGN was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: BGN were set to 27236923
Phenotypes for gene: BGN were set to Spondyloepimetaphyseal dysplasia, X-linked - MIM# 300106
Review for gene: BGN was set to GREEN
Added comment: Well-established gene-disease associated with X-linked spondyloepimetaphyseal dysplasia (SEMD)
Sources: Expert list, Literature
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
Skeletal dysplasia v0.102 UFSP2 Zornitza Stark Phenotypes for gene: UFSP2 were changed from Beukes Hip Dysplasia 142669, Spondyloepimetaphyseal dysplasia, Di Rocco type 617974 to Hip dysplasia, Beukes type, MIM#142669; Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974
Skeletal dysplasia v0.98 UFSP2 Zornitza Stark reviewed gene: UFSP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26428751, 28892125, 32755715; Phenotypes: Hip dysplasia, Beukes type, MIM#142669, Spondyloepimetaphyseal dysplasia, Di Rocco type, MIM# 617974; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Skeletal dysplasia v0.93 NEPRO Zornitza Stark gene: NEPRO was added
gene: NEPRO was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: NEPRO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEPRO were set to 26633546; 29620724; 31250547
Phenotypes for gene: NEPRO were set to Anauxetic dysplasia 3, MIM618853
Review for gene: NEPRO was set to AMBER
Added comment: PMIDs 26633546, 29620724: 2 families with the same homozygous missense variant, haplotype analysis confirmed the founder nature of the variant. PMID 31250547: 1 family with homozygous novel missense All 5 affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. No functional studies.
Sources: Literature
Skeletal dysplasia v0.69 FBLN1 Zornitza Stark reviewed gene: FBLN1: Rating: RED; Mode of pathogenicity: None; Publications: 11836357; Phenotypes: Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses MIM#608180; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Skeletal dysplasia v0.60 PRKG2 Zornitza Stark gene: PRKG2 was added
gene: PRKG2 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PRKG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PRKG2 were set to 33106379
Phenotypes for gene: PRKG2 were set to Acromesomelic dysplasia
Review for gene: PRKG2 was set to GREEN
Added comment: - PMID: 33106379 (2020) - Distinct homozygous variants in PRKG2 identified in two unrelated individuals, both with a skeletal dysplasia associated with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional studies showed both variants result in NMD and disrupt the downstream MAPK signalling pathway in response to FGF2. The role of cGKII, encoded by PRKG2, in skeletal growth has been established in several animal models (references provided in paper).
Sources: Literature
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
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
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
Skeletal dysplasia v0.24 RUNX2 Tiong Tan Added phenotypes Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly 156510; Cleidocranial dysplasia, forme fruste, dental anomalies only 119600; Cleidocranial dysplasia, forme fruste, with brachydactyly 119600; Cleidocranial dysplasia 119600 for gene: RUNX2
Skeletal dysplasia v0.24 MMP9 Tiong Tan Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9
Publications for gene MMP9 were updated from 28342220; 19615667 to 28342220; 19615667
Skeletal dysplasia v0.24 MMP13 Tiong Tan Added phenotypes Metaphyseal anadysplasia 1 602111; Spondyloepimetaphyseal dysplasia, Missouri type 602111; Metaphyseal dysplasia, Spahr type - 250400 for gene: MMP13
Skeletal dysplasia v0.24 PTH1R Tiong Tan Added phenotypes Failure of tooth eruption, primary 125350; Eiken syndrome 600002; Metaphyseal chondrodysplasia, Murk Jansen type 156400; Chondrodysplasia, Blomstrand type 215045 for gene: PTH1R
Skeletal dysplasia v0.24 RMRP Tiong Tan Added phenotypes Cartilage-hair hypoplasia 250250; Metaphyseal dysplasia without hypotrichosis 250460; Anauxetic dysplasia 607095 for gene: RMRP
Skeletal dysplasia v0.24 COL10A1 Tiong Tan Added phenotypes Metaphyseal chondrodysplasia, Schmid type 156500 for gene: COL10A1
Skeletal dysplasia v0.24 RUNX2 Tiong Tan Added phenotypes Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly 156510; Cleidocranial dysplasia, forme fruste, dental anomalies only 119600; Cleidocranial dysplasia, forme fruste, with brachydactyly 119600; Cleidocranial dysplasia 119600 for gene: RUNX2
Skeletal dysplasia v0.24 MMP9 Tiong Tan Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9
Publications for gene MMP9 were updated from 19615667; 28342220 to 28342220; 19615667
Skeletal dysplasia v0.24 MMP13 Tiong Tan Added phenotypes Metaphyseal anadysplasia 1 602111; Spondyloepimetaphyseal dysplasia, Missouri type 602111; Metaphyseal dysplasia, Spahr type - 250400 for gene: MMP13
Skeletal dysplasia v0.24 PTH1R Tiong Tan Added phenotypes Failure of tooth eruption, primary 125350; Eiken syndrome 600002; Metaphyseal chondrodysplasia, Murk Jansen type 156400; Chondrodysplasia, Blomstrand type 215045 for gene: PTH1R
Skeletal dysplasia v0.24 RMRP Tiong Tan Added phenotypes Cartilage-hair hypoplasia 250250; Metaphyseal dysplasia without hypotrichosis 250460; Anauxetic dysplasia 607095 for gene: RMRP
Skeletal dysplasia v0.24 COL10A1 Tiong Tan Added phenotypes Metaphyseal chondrodysplasia, Schmid type 156500 for gene: COL10A1
Skeletal dysplasia v0.23 RUNX2 Tiong Tan Source Victorian Clinical Genetics Services was added to RUNX2.
Added phenotypes Cleidocranial dysplasia, forme fruste, dental anomalies only 119600; Cleidocranial dysplasia, forme fruste, with brachydactyly 119600; Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly 156510; Cleidocranial dysplasia 119600 for gene: RUNX2
Skeletal dysplasia v0.23 MMP9 Tiong Tan Source Victorian Clinical Genetics Services was added to MMP9.
Source Expert Review Green was added to MMP9.
Mode of inheritance for gene MMP9 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9
Publications for gene MMP9 were updated from 28342220; 19615667 to 19615667; 28342220
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v0.23 MMP13 Tiong Tan Source Victorian Clinical Genetics Services was added to MMP13.
Added phenotypes Metaphyseal anadysplasia 1 602111; Spondyloepimetaphyseal dysplasia, Missouri type 602111; Metaphyseal dysplasia, Spahr type - 250400 for gene: MMP13
Skeletal dysplasia v0.23 PTH1R Tiong Tan Source Victorian Clinical Genetics Services was added to PTH1R.
Added phenotypes Metaphyseal chondrodysplasia, Murk Jansen type 156400; Eiken syndrome 600002; Failure of tooth eruption, primary 125350; Chondrodysplasia, Blomstrand type 215045 for gene: PTH1R
Skeletal dysplasia v0.23 RMRP Tiong Tan Source Victorian Clinical Genetics Services was added to RMRP.
Added phenotypes Metaphyseal dysplasia without hypotrichosis 250460; Cartilage-hair hypoplasia 250250; Anauxetic dysplasia 607095 for gene: RMRP
Skeletal dysplasia v0.23 COL10A1 Tiong Tan Source Victorian Clinical Genetics Services was added to COL10A1.
Mode of inheritance for gene COL10A1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Added phenotypes Metaphyseal chondrodysplasia, Schmid type 156500 for gene: COL10A1
Skeletal dysplasia v0.20 COL10A1 Kristin Rigbye reviewed gene: COL10A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 15880705, 31633898; Phenotypes: Metaphyseal chondrodysplasia, Schmid type, 156500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Skeletal dysplasia v0.7 RPL13 Zornitza Stark reviewed gene: RPL13: Rating: GREEN; Mode of pathogenicity: None; Publications: 31630789; Phenotypes: Spondyloepimetaphyseal Dysplasia with Severe Short Stature; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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
Skeletal dysplasia v0.0 UFSP2 Zornitza Stark gene: UFSP2 was added
gene: UFSP2 was added to Skeletal dysplasia. Sources: NHS GMS
Mode of inheritance for gene: UFSP2 was set to
Publications for gene: UFSP2 were set to 28892125; 26428751
Phenotypes for gene: UFSP2 were set to Beukes Hip Dysplasia 142669, Spondyloepimetaphyseal dysplasia, Di Rocco type 617974
Skeletal dysplasia v0.0 TRMT10A Zornitza Stark gene: TRMT10A was added
gene: TRMT10A was added to Skeletal dysplasia. Sources: Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TRMT10A was set to
Phenotypes for gene: TRMT10A were set to Microcephaly, short stature and impaired glucose metabolism, 616033
Skeletal dysplasia v0.0 IDH2 Zornitza Stark gene: IDH2 was added
gene: IDH2 was added to Skeletal dysplasia. Sources: Expert Review Red,NHS GMS
Mode of inheritance for gene: IDH2 was set to Unknown
Publications for gene: IDH2 were set to 22057234; 22057236; 24049096
Phenotypes for gene: IDH2 were set to D-2-hydroxyglutaric aciduria 2 613657; Ollier disease/ Dyschondroplasia 166000; Maffucci syndrome 614569; Enchondromatosis (Ollier) and Enchondromatosis with hermangiomata (Maffucci) 166000, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (614875)
Skeletal dysplasia v0.0 PAM16 Zornitza Stark gene: PAM16 was added
gene: PAM16 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Amber,Expert list
Mode of inheritance for gene: PAM16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAM16 were set to 27354339; 24786642
Phenotypes for gene: PAM16 were set to Spondylometaphyseal dysplasia, Megarbane-Dagher-Melike type 613320
Skeletal dysplasia v0.0 MMP9 Zornitza Stark gene: MMP9 was added
gene: MMP9 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Amber,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: MMP9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MMP9 were set to 28342220; 19615667
Phenotypes for gene: MMP9 were set to Metaphyseal anadysplasia 2 613073
Skeletal dysplasia v0.0 GPX4 Zornitza Stark gene: GPX4 was added
gene: GPX4 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Amber,Expert list,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: GPX4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPX4 were set to 24706940
Phenotypes for gene: GPX4 were set to Spondylometaphyseal dysplasia, Sedaghatian type 250220
Skeletal dysplasia v0.0 FBLN1 Zornitza Stark gene: FBLN1 was added
gene: FBLN1 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Amber
Mode of inheritance for gene: FBLN1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FBLN1 were set to 24084572
Phenotypes for gene: FBLN1 were set to Synpolydactyly, 3/3'4, associated with metacarpal and metatarsal synostoses 608180
Skeletal dysplasia v0.0 TRPV4 Zornitza Stark gene: TRPV4 was added
gene: TRPV4 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: TRPV4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TRPV4 were set to Digital arthropathy-brachydactyly, familial 606835; Parastremmatic dwarfism 168400; Scapuloperoneal spinal muscular atrophy 181405; SED, Maroteaux type 184095; Brachyolmia type 3 113500; Hereditary motor and sensory neuropathy, type IIc 606071; Spinal muscular atrophy, distal, congenital nonprogressive 600175; Metatropic dysplasia 156530; Spondylometaphyseal dysplasia, Kozlowski type 184252
Skeletal dysplasia v0.0 SFRP4 Zornitza Stark gene: SFRP4 was added
gene: SFRP4 was added to Skeletal dysplasia. Sources: NHS GMS,Literature,Expert Review Green
Mode of inheritance for gene: SFRP4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SFRP4 were set to 28100910; 27355534; 26273529; 27117872; 20174869; 24096177; 22965941; 22387305
Phenotypes for gene: SFRP4 were set to PYL; Pyle disease 265900; Metaphyseal dysplasia
Skeletal dysplasia v0.0 RUNX2 Zornitza Stark gene: RUNX2 was added
gene: RUNX2 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Expert Review Green,Radboud University Medical Center, Nijmegen,UKGTN,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: RUNX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RUNX2 were set to Cleidocranial dysplasia, forme fruste, with brachydactyly 119600; Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly 156510; Cleidocranial dysplasia, forme fruste, dental anomalies only 119600; Cleidocranial dysplasia 119600
Skeletal dysplasia v0.0 RPL13 Zornitza Stark gene: RPL13 was added
gene: RPL13 was added to Skeletal dysplasia. Sources: Literature,Expert Review Green
Mode of inheritance for gene: RPL13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPL13 were set to 31630789
Phenotypes for gene: RPL13 were set to Spondyloepimetaphyseal Dysplasia with Severe Short Stature
Skeletal dysplasia v0.0 RMRP Zornitza Stark gene: RMRP was added
gene: RMRP was added to Skeletal dysplasia. Sources: Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green
Mode of inheritance for gene: RMRP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RMRP were set to Metaphyseal dysplasia without hypotrichosis 250460; Anauxetic dysplasia 607095; Cartilage-hair hypoplasia 250250
Skeletal dysplasia v0.0 PTPN11 Zornitza Stark gene: PTPN11 was added
gene: PTPN11 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Expert Review Green,Radboud University Medical Center, Nijmegen,UKGTN,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: PTPN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTPN11 were set to LEOPARD syndrome 1 151100; Noonan syndrome 1 163950; Metachondromatosis 156250; LEOPARD syndrome 1 151100
Skeletal dysplasia v0.0 PTH1R Zornitza Stark gene: PTH1R was added
gene: PTH1R was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PTH1R was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: PTH1R were set to Eiken syndrome 600002; Chondrodysplasia, Blomstrand type 215045; Failure of tooth eruption, primary 125350; Metaphyseal chondrodysplasia, Murk Jansen type 156400
Skeletal dysplasia v0.0 PCYT1A Zornitza Stark gene: PCYT1A was added
gene: PCYT1A was added to Skeletal dysplasia. Sources: NHS GMS,Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: PCYT1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PCYT1A were set to Spondylometaphyseal dysplasia with cone-rod dystrophy 608940; Spondylometaphyseal dysplasia with cone-rod dystrophy 608940
Skeletal dysplasia v0.0 PAPSS2 Zornitza Stark gene: PAPSS2 was added
gene: PAPSS2 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: PAPSS2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PAPSS2 were set to Brachyolmia 4 with mild epiphyseal and metaphyseal changes 612847
Skeletal dysplasia v0.0 NKX3-2 Zornitza Stark gene: NKX3-2 was added
gene: NKX3-2 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,UKGTN
Mode of inheritance for gene: NKX3-2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NKX3-2 were set to Spondylo-megaepiphyseal-metaphyseal dysplasia 613330
Skeletal dysplasia v0.0 NANS Zornitza Stark gene: NANS was added
gene: NANS was added to Skeletal dysplasia. Sources: NHS GMS,Literature,Expert Review Green
Mode of inheritance for gene: NANS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NANS were set to 27213289
Phenotypes for gene: NANS were set to Spondyloepimetaphyseal dysplasia, Camera-Genevieve type 610442
Skeletal dysplasia v0.0 MMP13 Zornitza Stark gene: MMP13 was added
gene: MMP13 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: MMP13 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MMP13 were set to 24648384
Phenotypes for gene: MMP13 were set to Spondyloepimetaphyseal dysplasia, Missouri type 602111; Metaphyseal dysplasia, Spahr type - 250400; Metaphyseal anadysplasia 1 602111
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
Skeletal dysplasia v0.0 MAP3K7 Zornitza Stark gene: MAP3K7 was added
gene: MAP3K7 was added to Skeletal dysplasia. Sources: NHS GMS,Literature,Expert Review Green
Mode of inheritance for gene: MAP3K7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MAP3K7 were set to 27426733
Phenotypes for gene: MAP3K7 were set to Frontometaphyseal dysplasia 2, 617137
Mode of pathogenicity for gene: MAP3K7 was set to Other - please provide details in the comments
Skeletal dysplasia v0.0 KIF22 Zornitza Stark gene: KIF22 was added
gene: KIF22 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,UKGTN
Mode of inheritance for gene: KIF22 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF22 were set to Spondyloepimetaphyseal dysplasia with joint laxity, type 2 603546
Skeletal dysplasia v0.0 IDH1 Zornitza Stark gene: IDH1 was added
gene: IDH1 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: IDH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IDH1 were set to 22057234; 22025298; 22057236; 24049096
Phenotypes for gene: IDH1 were set to Ollier disease/ Dyschondroplasia 166000; Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria 614875; Maffucci syndrome 614569
Mode of pathogenicity for gene: IDH1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Skeletal dysplasia v0.0 GJA1 Zornitza Stark gene: GJA1 was added
gene: GJA1 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: GJA1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GJA1 were set to Oculodentodigital dysplasia 164200; Erythrokeratodermia variabilis et progressiva 133200; Palmoplantar keratoderma with congenital alopecia 104100; Hypoplastic left heart syndrome 1 241550; Oculodentodigital dysplasia, autosomal recessive 257850; Craniometaphyseal dysplasia, autosomal recessive 218400; Syndactyly, type III 186100
Skeletal dysplasia v0.0 FN1 Zornitza Stark gene: FN1 was added
gene: FN1 was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FN1 were set to 29100092; 30599297
Phenotypes for gene: FN1 were set to Spondylometaphyseal dysplasia, corner fracture type 184255
Mode of pathogenicity for gene: FN1 was set to Other
Skeletal dysplasia v0.0 FLNA Zornitza Stark gene: FLNA was added
gene: FLNA was added to Skeletal dysplasia. Sources: NHS GMS,Expert Review Green
Mode of inheritance for gene: FLNA 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: FLNA were set to Frontometaphyseal dysplasia 305620; Otopalatodigital syndrome, type II -304120; Osteodysplasty Melnick Needles 309350 XLD; Melnick Needles syndrome 309350; Otopalatodigital syndrome, type II 304120 XLD; Frontometaphyseal dysplasia 305620 XLR; Terminal osseous dysplasia 300244; Otopalatodigital syndrome, type I -311300
Skeletal dysplasia v0.0 FGF16 Zornitza Stark gene: FGF16 was added
gene: FGF16 was added to Skeletal dysplasia. Sources: Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green
Mode of inheritance for gene: FGF16 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: FGF16 were set to Metacarpal 4-5 fusion 309630; Metacarpal 4-5 fusion 309630
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
Skeletal dysplasia v0.0 COL10A1 Zornitza Stark gene: COL10A1 was added
gene: COL10A1 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Expert Review Green
Mode of inheritance for gene: COL10A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: COL10A1 were set to Metaphyseal chondrodysplasia, Schmid type 156500
Skeletal dysplasia v0.0 C21orf2 Zornitza Stark gene: C21orf2 was added
gene: C21orf2 was added to Skeletal dysplasia. Sources: NHS GMS,Literature,Expert list,Expert Review Green
Mode of inheritance for gene: C21orf2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C21orf2 were set to 26974433
Phenotypes for gene: C21orf2 were set to Axial Spondylometaphyseal Dysplasia 602271; Spondylometaphyseal dysplasia, axial 602271
Skeletal dysplasia v0.0 B3GALT6 Zornitza Stark gene: B3GALT6 was added
gene: B3GALT6 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Expert Review Green
Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: B3GALT6 were set to Ehlers-Danlos syndrome, progeroid type, 2 615349; Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures 271640
Skeletal dysplasia v0.0 ANKH Zornitza Stark gene: ANKH was added
gene: ANKH was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green,UKGTN,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: ANKH was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ANKH were set to Chondrocalcinosis 2 118600; Craniometaphyseal dysplasia 123000
Skeletal dysplasia v0.0 ACAN Zornitza Stark gene: ACAN was added
gene: ACAN was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,NHS GMS,Radboud University Medical Center, Nijmegen,Expert Review Green
Mode of inheritance for gene: ACAN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ACAN were set to 24762113
Phenotypes for gene: ACAN were set to Spondyloepiphyseal dysplasia, Kimberley type 608361; Osteochondritis dissecans, short stature, and early-onset osteoarthritis 165800; Spondyloepimetaphyseal dysplasia, aggrecan type 61283