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| Skeletal dysplasia v4.16 | PKDCC | Arina Puzriakova Phenotypes for gene: PKDCC were changed from Rhizomelia; dysmorphism to Rhizomelic limb shortening with dysmorphic features, OMIM:618821 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v3.2 | SHOX | Arina Puzriakova Phenotypes for gene: SHOX were changed from Langer mesomelic dysplasia 249700; Short stature, idiopathic familial 300582; Leri-Weill dyschondrosteosis 127300 to Langer mesomelic dysplasia, OMIM:249700 (PR); Leri-Weill dyschondrosteosis, OMIM:127300 (PD); Short stature, idiopathic familial, OMIM:300582; Dorsolateral bowed, short radii; Bowing and curving of radius; Radioulnar shortening | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.226 | RAD21 | Arina Puzriakova Added comment: Comment on list classification: Although limb abnormalities are a common feature of CdLS, only minor skeletal anomalies are associated with RAD21 variants. Other prominent features such as ID are more likely to prompt testing and therefore maintaining the Amber rating on skeletal panels for now. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.202 | DVL2 | Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for consideration for GREEN rating following GMS review. Although only 1 case has been reported, supporting evidence comes from canine data and from the fact that similar causative variants associated with Robinow syndrome have been found in the other two Dishevelled paralogs. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.161 | HHAT |
Eleanor Williams changed review comment from: Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM. PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous. PMID:30912300 - Abdel-Salam et al 2019 - report two siblings with progressive microcephaly (-6 SD at age 6 and age 3 for the 2 siblings respectively), early infantile onset seizures, and cerebellar vermis hypoplasia but notably without dwarfism and gonadal dysgenesis. Skeletal x-rays of both siblings showed nlarged epiphyses and metaphyses, thinning of the lateral 1/3 of clavicles and trapezoidal vertebral bodies. WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT which is in the conserved MBOAT domain. Both parents were heterozygous for the variant. PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped tho-rax, short and angel-shaped epiphyses of hands and feet) and midfac eretrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a singlec entral incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.); to: Associated with Nivelon-Nivelon-Mabille syndrome #600092 (AR) in OMIM. PMID:24784881 - Callier et al 2014 - report a family with 2 siblings with Disorder of Sex Development (DSD) and chondrodysplasia (Nivelon-Nivelon-Mabille syndrome). The first sibling (46,XY karyotype) displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly (-7.5 SD at age 16 (PMID:15578577) with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs. Complete gonadal dysgenesis ( including normal external female genitalia, lack of pubertal development, primary amenorrhea, and hypergonadotrophic hypogonadism) and intellectual disability is also noted. The second sibling (46,XX karyotype) had histologically normal ovaries and similar phenotypic abnormalities including severe dwarfism and generalized chondrodysplasia. Using WES a homozygous missense variant was found NM_001122834:c.860G>T:p.(Gly287Val) in HHAT in the first sibling which is in the conserved MBOAT domain. The parents were heterozygous. They also found that mice lacking functional Hhat show a similar phenotype as the syndromic 46,XY DSD patient including testicular dysgenesis and skeletal defects. PMID:30912300 - Abdel-Salam et al 2019 - report two siblings with progressive microcephaly (-6 SD at age 6 and age 3 for the 2 siblings respectively), early infantile onset seizures, and cerebellar vermis hypoplasia but notably without dwarfism and gonadal dysgenesis. Skeletal x-rays of both siblings showed enlarged epiphyses and metaphyses, thinning of the lateral 1/3 of clavicles and trapezoidal vertebral bodies. Both sisters had a normal female karyotype (46, XX). WES found a homozygous missense (c.770T>C, p.[Leu257Pro]) HHAT which is in the conserved MBOAT domain. Both parents were heterozygous for the variant. PMID: 33749989 - Pande et al 2021 - report multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del), in exon 5 of HHAT in the living proband. She shows severe microphthalmia, microcephaly (−8 SD head circumference at age 7), skeletal dysplasia (narrow bell-shaped tho-rax, short and angel-shaped epiphyses of hands and feet) and midfac eretrusion, short columella with a groove at the base, prominent ears, long philtrum, depressed nasal bridge, everted lower lip, and a singlec entral incisor. She also has complete sex reversal (karyotype of 46, XY, normal internal organs including uterus and ovaries.) |
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| Skeletal dysplasia v2.137 | SCUBE3 | Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.87 | NMNAT1 |
Zornitza Stark gene: NMNAT1 was added gene: NMNAT1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: NMNAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NMNAT1 were set to 32533184 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 GREEN gene: NMNAT1 was marked as current diagnostic Added comment: The association with LCA is well established. New report of a syndromic LCA disorder and note also unusual variant type. Three families, but two are distantly related (shared haplotype). The affected children in those two 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. Sources: Literature |
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| Skeletal dysplasia v2.83 | EN1 |
Zornitza Stark gene: EN1 was added gene: EN1 was added to Skeletal dysplasia. Sources: Literature 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; ENDOVE syndrome, limb-brain type, MIM# 619218 Review for gene: EN1 was set to GREEN gene: EN1 was marked as current diagnostic 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. 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 v2.80 | PKDCC | Michael Oldridge reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 30478137; Phenotypes: rhizomelic limb shortening, facial dysmorphism; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.52 | PKDCC | Eleanor Williams reviewed gene: PKDCC: Rating: AMBER; Mode of pathogenicity: None; Publications: 30478137, 19097194; Phenotypes: Rhizomelic limb shortening with dysmorphic features OMIM:618821, rhizomelic limb shortening with dysmorphic features MONDO:0032935; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.36 | ANAPC1 |
Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating. Sources: Literature; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating. Have tagged with "for-review" so that GMS could review whether this gene is appropriate for the panel or not. Sources: Literature |
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| Skeletal dysplasia v2.35 | ANAPC1 |
Ivone Leong gene: ANAPC1 was added gene: ANAPC1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: ANAPC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ANAPC1 were set to 31303264 Phenotypes for gene: ANAPC1 were set to Rothmund Thomson syndrome type 1, OMIM:618625, MONDO:0016368 Review for gene: ANAPC1 was set to AMBER Added comment: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype. PMID: 31303264 describes 10 patients from 7 families with Rothmund-Thomson syndrome. 4 of 7 families are homozygous for the same intronic variant (c.2705-198C-T) and the remaining 3 affected families are compound heterozygous (c.2705-198C-T with another variant in the gene). 5/10 affected individuals have skeletal abnormalities; however, the phenotype is weak. Therefore, this gene has been given an Amber rating. Sources: Literature |
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| Skeletal dysplasia v2.25 | PRKG2 |
Arina Puzriakova gene: PRKG2 was added gene: PRKG2 was added to Skeletal dysplasia. Sources: Literature watchlist tags were added to gene: PRKG2. 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 AMBER 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 |
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| Skeletal dysplasia v2.10 | GNPNAT1 |
Arina Puzriakova changed review comment from: 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: Literature; to: 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. Sources: Literature |
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| Skeletal dysplasia v2.10 | GNPNAT1 |
Arina Puzriakova changed review comment from: 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. Sources: Literature; to: 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: Literature |
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| Skeletal dysplasia v2.10 | GNPNAT1 |
Arina Puzriakova gene: GNPNAT1 was added gene: GNPNAT1 was added to Skeletal dysplasia. Sources: Literature 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 RED 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. Sources: Literature |
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| Skeletal dysplasia v2.9 | PLEKHM1 |
Eleanor Williams commented on gene: PLEKHM1: Provisionally associated with ?Osteopetrosis, autosomal recessive 6 #611497 and Osteopetrosis, autosomal dominant 3 #618107 in OMIM. 2 biallelic and 2 monoallelic cases reported. Limited family segregation data and generally targeted sequencing of only a few candidate genes. A mouse model supports the role for this protein in bone re-absorption. BIALLELIC PMID: 17404618 - Van Wesenbeeck et al 2007 - report that loss of function variants in the PLEKHM1 gene are responsible for the osteopetrotic phenotype of the incisors absent (ia) rat. They then screened the coding sequence of the PLEKHM1 gene in 43 patients diagnosed with various forms of osteopetrosis and identified a patient with a homozygous G→A transition at position +1 of the donor splice site of intron 3. She was diagnosed with an autosomal-recessive intermediate form of the disease. Her parents, carriers of the mutation, were related to each other and were clinically normal. The oldest brother was heterozygous for the mutation and was clinically and radiologically normal. The youngest brother was homozygous for the mutation but had not yet developed clinical symptoms. PMID: 28290981 - Moore et al 2017 - report 19 year old white male with history of fractures, as did 2 of his brothers, presenting with clinical osteopetrosis. Genetic testing using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis, revealed 2 heterozygous missense mutations in PLEKHM1 (exon 4 and exon 7). No segregation data. MONOALLELIC PMID: 27291868 - Bo et al 2016 - report a middle‐aged Chinese man who presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in BMD. A novel de novo heterozygous mutation ( c.3051_3052delCA) in the PLEKHM1 gene was identified, after initial screening of ClCN7 and TNFSF11 genes found no disease causing variants. The patient's unaffected parents and children were also screen and were not found to have the deletion. PMID: 17997709 - Del Fattore et al 2008 - describe a new heterozygous missense mutation (R714C) in the PLEKHM1 gene in a female Italian patient with generalized osteopenia and localized osteosclerosis, with a diagnosis of osteopetrosis of the skull, However they state that it is NOT a case of osteopetrosis, because in the patient, urine CTX, a marker of in vivo bone resorption, was normal, and in vitro assays of osteoclast formation and resorptive function showed no abnormalities. She was screened for variants only in ClC‐7 and PLEKHM1. No other family members were available for analysis. MOUSE MODEL PMID: 27777970 - Fujiwara et al 2016 - Plekhm1-deficient mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Loss of Plekhm1 increased cancellous bone mass due to decreased bone resorption without obvious defects in other tissues and organs. |
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| Skeletal dysplasia v2.4 | NXN |
Ellen McDonagh changed review comment from: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling. Sources: Literature, Expert Review; to: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes. NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling. |
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| Skeletal dysplasia v2.4 | NXN |
Ellen McDonagh gene: NXN was added gene: NXN was added to Skeletal dysplasia. Sources: Literature,Expert Review Mode of inheritance for gene: NXN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NXN were set to 29276006 Phenotypes for gene: NXN were set to Robinow syndrome, autosomal recessive 2 618529 Review for gene: NXN was set to AMBER Added comment: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling. Sources: Literature, Expert Review |
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| Skeletal dysplasia v1.340 | ALX1 |
Eleanor Williams commented on gene: ALX1: This gene is provisionally associated with ?Frontonasal dysplasia 3 (#613456) in OMIM. Has a confirmed association with FRONTONASAL DYSPLASIA TYPE 3 in Gene2Phenotype. PMID: 20451171 - Uz et al. (2010) - 2 families presenting with autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. In one family they found a three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene. In the second family a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene was found. PMID: 27324866 - Ullah et al 2017 - report a consanguineous family from Pakistan with four individuals presenting a milder form of Frontonasal dysplasia. Using exome sequencing, a homozygous splice acceptor site variant has been identified in the ALX1 gene. The affected individuals had ptosis (drooping upper eyelid), small and upslanting palpebral fissures, blepharophimosis, broad nasal root, wide prominent nasal bridge, short and wide nasal ridge, broad columella, smooth philtrum, and mouth protrusion accompanied by teeth protrusion NOTE: no clefting reported in the individuals from this family. PMID: 26610632 - Lyons et al 2015 - The “Contemporary” Burmese lineage of cats has a more brachycephalic head type. Offspring from “Contemporary” style mating produced a craniofacial defect in 25% of offspring (Noden and Evans, 1986; Sponenberg and Graf-Webster, 1986). The abnormality is characterized by agenesis of all derivatives of the medial nasal prominence; lateral duplication of most derivatives of the maxillary process; including the canine teeth and whiskers fields; telencephalic meningoencephalocele; and secondary ocular degeneration . The midline facial defect is autosomal recessive, however, carriers of the mutation are more brachycephalic individuals than wildtype, The entire ALX1 CDS sequence was analyzed in ten cats, including five affected Burmese and five controls. A 12 bp deletion (c.496delCTCTCAGGACTG) was identified in the coding region of ALX1. All the unaffected cats in the pedigree were confirmed to be homozygous wild-type or carrier of the 12 bp deletion while all the affected cats were homozygous for the identified variant. The average CDS homology between human and cat is 93.8% and the protein identity is 97.5%. |
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| Skeletal dysplasia v1.220 | COG1 |
Eleanor Williams changed review comment from: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM.; to: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM. Clinical features include short stature, several skeletal features such as scoliosis and vertebral abnormalities. PMID: 16537452 - Foulquier et al 2006 - describe a patient with a mild form of congenital disorder of glycosylation type II with a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. Both parents were shown to be heterozygous for this mutation. Her skeletal features included small hands and feet, rhizomelic short stature. PMID: 19008299 - Zeevaert et al 2009 - two patients (one with consanguineous Greek-Turkish parents, the other with unrelated Bulgarian parents) with a cerebrocostomandibular-like syndrome and an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Patient 1's characteristics included multiple congenital abnormalities including Pierre-Robin sequence (cleft palate, micrognathia and glossoptosis), costovertebral anomalies including osteopenia, ribfusions and posterior rib gaps, butterfly vertebrae, misalignment of the vertebrae and a clubfoot on the right. Patient 2 presented with rhizomelic shortening of upper limbs, ulnar deviation of fingers, thoracic scoliosis, hypospadias-I and left-side cryptorchidism among other features. 3 unrelated cases. |
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| Skeletal dysplasia v1.213 | KIAA0753 |
Eleanor Williams gene: KIAA0753 was added gene: KIAA0753 was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: KIAA0753 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KIAA0753 were set to 29138412; 28220259; 26643951 Phenotypes for gene: KIAA0753 were set to ?Orofaciodigital syndrome XV 617127; Joubert syndrome; Short-rib skeletal dysplasia Review for gene: KIAA0753 was set to GREEN Added comment: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant. PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency but no oral or digital anomalies. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant. Sources: Other |
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| Skeletal dysplasia v1.210 | DHCR7 | Eleanor Williams Added comment: Comment on list classification: This ciliopathy gene is being added to the Skeletal dysplasia panel after discussion with the Genomics England clinical team. Smith-Lemli-Optiz syndrome includes features such as limb shortening as well as abnormalities of the hands and feet. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.209 | DHCR7 |
Eleanor Williams gene: DHCR7 was added gene: DHCR7 was added to Skeletal dysplasia. Sources: Other Mode of inheritance for gene: DHCR7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DHCR7 were set to 9634533 Phenotypes for gene: DHCR7 were set to Smith-Lemli-Opitz syndrome 270400 Review for gene: DHCR7 was set to GREEN Added comment: Associated with Smith-Lemli-Opitz syndrome in OMIM. They describe this as "an autosomal recessive multiple congenital malformation and mental retardation syndrome." Several skeletal features are listed in the clinical features in OMIM including limb shortening, Hip dislocation and subluxation, and abnormalities of the hands and feet. Sources: Other |
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| Skeletal dysplasia v1.204 | TMEM67 |
Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.; to: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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| Skeletal dysplasia v1.201 | NIN | Eleanor Williams Classified gene: NIN as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.201 | NIN | Eleanor Williams Added comment: Comment on list classification: Changing rating from green to red, in light of Zornitza Stark's red review. Evidence is not strong. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.201 | NIN | Eleanor Williams Gene: nin has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | MMP9 |
Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Summary: only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification. |
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| Skeletal dysplasia v1.192 | NIN | Zornitza Stark reviewed gene: NIN: Rating: RED; Mode of pathogenicity: None; Publications: 22933543, 23665482; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | NIN |
Eleanor Williams changed review comment from: PMID: 22933543 - Dauber et al. (2012) -2 sisters with severe short stature, microcephaly, and developmental delay (Seckel syndrome-7) were identified to have compound heterozygosity for missense mutations in the NIN gene (Q1222R; N1709S) PMID: 23665482 -Grosch et al (2013) - in a consanguineous family with a phenotype resembling Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) they identified homozygous missense mutations in the two nearby genes NIN and POLE2 which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. They present evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The NIN variant is classified as a VUS in OMIM. ; to: PMID: 22933543 - Dauber et al. (2012) -2 sisters with severe short stature, microcephaly, and developmental delay (Seckel syndrome-7) were identified to have compound heterozygosity for missense mutations in the NIN gene (Q1222R; N1709S). The p.N1709S is a novel variant that is not present in Single Nucleotide Polymorphism database, 1000 Genomes pilot data, or the NHLBI exome variant server. The p.Q1222R was present only in the 1000 Genomes pilot data with an overall minor allele frequency of 0.001 (0.005 in the Americas subcohort). In patient derived primary dermal fibroblasts, the compound heterozygous NIN defects did not disrupt Ninein expression or localization or obviously affect mitotic functions. But zebrafish nin morphilino knockdowns include phenotypes such as reduced growth and altered patterning of the skull, consistent with general phenotypic characteristics of MPD. PMID: 23665482 -Grosch et al (2013) - in a consanguineous family with a phenotype resembling Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) they identified homozygous missense mutations in the two nearby genes NIN and POLE2 which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. They present evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The NIN variant is classified as a VUS in OMIM. |
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| Skeletal dysplasia v1.192 | IFT43 |
Eleanor Williams changed review comment from: Associated with ?Cranioectodermal dysplasia 3 (#614099) and Short-rib thoracic dysplasia 18 with polydactyly (#617866) in OMIM and with CRANIOECTODERMAL DYSPLASIA TYPE 3 (confirmed) in Gene2Phenotype. PMID: 21378380- Arts et al. 2011 - 1 case . 2 siblings from a consanguineous family of Moroccan descent with cranioectodermal dysplasia (Sensenbrenner syndrome). The reported phenotype includes Rhizomelic shortening of limbs, narrow thorax, toe syndactyly, brachydactyly, and polydactyly (one sibling). Following genome-wide homozygosity mapping two candidate genes were analyzed and a homozygous missense mutation in the translation initiation codon of the IFT43 gene was identified. Fibroblasts from one of the affected siblings (II:2) show a typical IFT-A defect (ie, accumulation of IFT-B complex proteins in the ciliary tip. PMID: 28400947 - Duran et al. 2017- 2 cases - in 3 affected individuals from 2 unrelated families with short-rib thoracic dysplasia with polydactyly thye identified homozygosity for missense mutations in the IFT143 gene, M1K and W179R. PMID: 26892345 - Stokman et al 2016 - 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. They de novo 4.5-Mb microdeletion which contains 65 protein-coding genes, including the ciliary gene IFT43. Immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport.; to: Associated with ?Cranioectodermal dysplasia 3 (#614099) and Short-rib thoracic dysplasia 18 with polydactyly (#617866) in OMIM and with CRANIOECTODERMAL DYSPLASIA TYPE 3 (confirmed) in Gene2Phenotype. PMID: 21378380- Arts et al. 2011 - 1 case . 2 siblings from a consanguineous family of Moroccan descent with cranioectodermal dysplasia (Sensenbrenner syndrome). The reported phenotype includes Rhizomelic shortening of limbs, narrow thorax, toe syndactyly, brachydactyly, and polydactyly (one sibling). Following genome-wide homozygosity mapping two candidate genes were analyzed and a homozygous missense mutation in the translation initiation codon of the IFT43 gene was identified. Fibroblasts from one of the affected siblings (II:2) show a typical IFT-A defect (ie, accumulation of IFT-B complex proteins in the ciliary tip. PMID: 28400947 - Duran et al. 2017- 2 cases - in 3 affected individuals from 2 unrelated families with short-rib thoracic dysplasia with polydactyly they identified homozygosity for missense mutations in the IFT143 gene, M1K and W179R. PMID: 26892345 - Stokman et al 2016 - 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. They de novo 4.5-Mb microdeletion which contains 65 protein-coding genes, including the ciliary gene IFT43. Immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport. |
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| Skeletal dysplasia v1.182 | MMP9 |
Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9. Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification. |
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| Skeletal dysplasia v1.168 | ADAMTS10 |
Eleanor Williams commented on gene: ADAMTS10: Associated with Weill-Marchesani syndrome 1, recessive (#277600) in OMIM. PMID: 15368195 - Dagoneau et al. 2004 - 3 cases. following homozygosity-mapping strategy in two consanguineous families from Lebanon and Saudi Arabia with Weill-Marchesani syndrome they selected ADAMTS10 for further sequencing. They found three distinct mutations of the ADAMTS10 gene in these two families and in one sporadic WMS case (one nonsense mutation (R237X) and two splice-site mutations). The variants segregated with the disease in the familial cases. All probands fulfilled the criteria for WMS with short stature, brachydactyly, limitation of joint movement, microspherophakia, dislocated lenses, severe myopia, and glaucoma. PMID: 19836009 - Morales et al. 2009 - 2 cases. Two families which met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10 (c.1553 G > A (p.G518D) and c.2098 G > T (p.G700C)). PMID: 30060141 - Mularczyk et al 2018 - A mouse model containing a truncation mutation on ADAMS10 seen in WMS patients was created. Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation. |
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| Skeletal dysplasia v1.168 | TMEM67 |
Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.; to: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case: PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 - 3 out of 22 cases show polydactyly: PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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| Skeletal dysplasia v1.168 | TMEM67 |
Eleanor Williams commented on gene: TMEM67: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361). RHYNS syndrome - 1 case PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents. PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done. Meckel syndrome 3 PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families. PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family. |
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| Skeletal dysplasia v1.167 | NIN |
Eleanor Williams changed review comment from: PMID: 22933543 - Dauber et al. (2012) -2 sisters with severe short stature, microcephaly, and developmental delay (Seckel syndrome-7) were identified to have compound heterozygosity for missense mutations in the NIN gene (Q1222R; N1709S) PMID: 23665482 -Grosch et al (2013) - in a consanguineous family with a phenotype resembling Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) they identified homozygous missense mutations in the two nearby genes NIN and POLE2 which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. They present evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype.; to: PMID: 22933543 - Dauber et al. (2012) -2 sisters with severe short stature, microcephaly, and developmental delay (Seckel syndrome-7) were identified to have compound heterozygosity for missense mutations in the NIN gene (Q1222R; N1709S) PMID: 23665482 -Grosch et al (2013) - in a consanguineous family with a phenotype resembling Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) they identified homozygous missense mutations in the two nearby genes NIN and POLE2 which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. They present evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The NIN variant is classified as a VUS in OMIM. |
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| Skeletal dysplasia v1.166 | IFT43 |
Eleanor Williams commented on gene: IFT43: Associated with ?Cranioectodermal dysplasia 3 (#614099) and Short-rib thoracic dysplasia 18 with polydactyly (#617866) in OMIM and with CRANIOECTODERMAL DYSPLASIA TYPE 3 (confirmed) in Gene2Phenotype. PMID: 21378380- Arts et al. 2011 - 1 case . 2 siblings from a consanguineous family of Moroccan descent with cranioectodermal dysplasia (Sensenbrenner syndrome). The reported phenotype includes Rhizomelic shortening of limbs, narrow thorax, toe syndactyly, brachydactyly, and polydactyly (one sibling). Following genome-wide homozygosity mapping two candidate genes were analyzed and a homozygous missense mutation in the translation initiation codon of the IFT43 gene was identified. Fibroblasts from one of the affected siblings (II:2) show a typical IFT-A defect (ie, accumulation of IFT-B complex proteins in the ciliary tip. PMID: 28400947 - Duran et al. 2017- 2 cases - in 3 affected individuals from 2 unrelated families with short-rib thoracic dysplasia with polydactyly thye identified homozygosity for missense mutations in the IFT143 gene, M1K and W179R. PMID: 26892345 - Stokman et al 2016 - 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. They de novo 4.5-Mb microdeletion which contains 65 protein-coding genes, including the ciliary gene IFT43. Immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport. |
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| Skeletal dysplasia v1.159 | MMP9 |
Eleanor Williams commented on gene: MMP9: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family. PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F). PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9. Only 2 cases reported, 3rd had variant in MMP13 not MMP9. |
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| Skeletal dysplasia v1.155 | XYLT2 |
Eleanor Williams commented on gene: XYLT2: PMID: 26027496 - Munns et al 2015 - 3 patients from 2 unrelated families with bone fragility, hearing impairment, cardiac septal defects, and learning difficulties (spondyloocular syndrome). Identified homozygosity for a 1-bp duplication and a 1-bp deletion, respectively. The mutations, which segregated with disease in each family, were not found in public variant databases. PMID: 26987875- Taylan et al 2016 - report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. |
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| Skeletal dysplasia v1.155 | NIN |
Eleanor Williams commented on gene: NIN: PMID: 22933543 - Dauber et al. (2012) -2 sisters with severe short stature, microcephaly, and developmental delay (Seckel syndrome-7) were identified to have compound heterozygosity for missense mutations in the NIN gene (Q1222R; N1709S) PMID: 23665482 -Grosch et al (2013) - in a consanguineous family with a phenotype resembling Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) they identified homozygous missense mutations in the two nearby genes NIN and POLE2 which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. They present evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. |
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| Skeletal dysplasia v1.153 | NIN |
Eleanor Williams Added phenotypes Seckel syndrome 7 614851 for gene: NIN Publications for gene NIN were changed from 23665482; 22933543 to 22933543; 23665482 |
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| Skeletal dysplasia v1.147 | NIN | Tracy Lester reviewed gene: NIN: Rating: AMBER; Mode of pathogenicity: ; Publications: 22933543, 23665482; Phenotypes: Seckel syndrome 7 614851; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.146 | NIN | Eleanor Williams reviewed gene: NIN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.145 | NIN |
Eleanor Williams Source NHS GMS was added to NIN. Rating Changed from Green List (high evidence) to Green List (high evidence) |
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| Skeletal dysplasia v1.107 | PDE3A |
Rachel Jones gene: PDE3A was added gene: PDE3A was added to Unexplained skeletal dysplasia. Sources: Literature Mode of inheritance for gene: PDE3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PDE3A were set to PMID: 25961942; 9696728 Phenotypes for gene: PDE3A were set to Hypertension and brachydactyly syndrome 112410 Penetrance for gene: PDE3A were set to Complete Mode of pathogenicity for gene: PDE3A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: PDE3A was set to GREEN Added comment: Mutations appear to be gain of function missense as per PMID 25961942*. 6 missense variants identified in unrelated families with dominant hypertension with brachydactyly (HTNB) *Article link https://www.nature.com/articles/ng.3302 The article PMID: 9696728 gives more information about the clinical phenotype - their Canadian and American families showed linkage to an area of chromosome 12p containing PDE3A, as had a previous Turkish family. http://annals.org/aim/fullarticle/711593/families-autosomal-dominant-brachydactyly-type-e-short-stature-severe-hypertension. Sources: Literature |
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| Skeletal dysplasia v1.105 | ISCA-37406-Loss |
Louise Daugherty Region: ISCA-37406-Loss was added Region: ISCA-37406-Loss was added to Unexplained skeletal dysplasia. Sources: ClinGen,Expert Review Green Mode of inheritance for Region: ISCA-37406-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37406-Loss were set to 10573006; 16783566 Phenotypes for Region: ISCA-37406-Loss were set to PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes; 610543 |
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