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| Skeletal dysplasia v1.115 | LRRFIP1 |
chirag patel gene: LRRFIP1 was added gene: LRRFIP1 was added to Skeletal dysplasia. Sources: Other deep intronic tags were added to gene: LRRFIP1. Mode of inheritance for gene: LRRFIP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LRRFIP1 were set to Spondylodysplastic-erosive early-onset scoliosis Review for gene: LRRFIP1 was set to RED Added comment: ESHG 2026 Multiple individuals from 1 large multigenerational family with early-onset scoliosis, with a unique pattern of spondylodysplastic elements and progressive endplate erosion. Penetrance was 100% in the family. Linkage analysis and WGS identified a rare noncoding variant in the regulatory element in intron 1 of the LRRFIP1 gene (c.96+34737C>T). The variant segregated with disease in the family. Short- and long-read RNA sequencing in patient fibroblasts showed altered transcription factor binding and alteration of relative LRRFIP1-isoform expression. Differential gene expression analyses in patient fibroblasts showed alterations in Wnt-signaling during somitogenesis, extracellular matrix organization and TNF-a/NF-kb signaling, partially overlapping with features of common spinal disorders such as Ankylosing Spondylitis. Lrrfip1-knockout mouse had a significantly increased prevalence of kyphoscoliosis. Rare variant enrichment analysis using genome data from UK Biobank participants showed significant enrichment of LRRFIP1-variants in individuals with idiopathic scoliosis. Sources: Other |
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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 v1.1 | 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 | CRIPT | Gene migrated from ENSG00000119878 to ENSG00000119878 (gene set migration) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.406 | CRIPT | chirag patel Marked gene: CRIPT as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.406 | CRIPT | chirag patel Gene: cript has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.405 | chirag patel Copied gene CRIPT from panel Microcephalic Primordial Dwarfism and Slender bone dysplasias | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v0.405 | CRIPT |
chirag patel gene: CRIPT was added gene: CRIPT was added to Skeletal dysplasia. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRIPT were set to 24389050; 27250922; 36630262; 37013901 Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002 |
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| 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 v0.366 | 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 |
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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 v0.289 | 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 |
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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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