| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Skeletal dysplasia v5.4 | CBFB |
Sarah Leigh gene: CBFB was added gene: CBFB was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber Q2_24_promote_green, Q2_24_MOI, Q2_24_NHS_review tags were added to gene: CBFB. Mode of inheritance for gene: CBFB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CBFB were set to 36241386 Phenotypes for gene: CBFB were set to Cleidocranial dysplasia 2, OMIM:620099; cleidocranial dysplasia 2, MONDO:0859307 Penetrance for gene: CBFB were set to Complete |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.49 | TP53 |
Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS. This gene is rated as red, because the variants are somatic, occurring in the tumour.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.49 | TP53 |
Sarah Leigh changed review comment from: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.; to: PMID: 33147331 reports inactivating somatic TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS. This gene is rated as red, because the variants are somatic, occurring in the tumour. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.45 | TP53 |
Sarah Leigh edited their review of gene: TP53: Added comment: PMID: 33147331 reports inactivating TP53 variants in dedifferentiated components of dedifferentiated chondrosarcoma. Due to the distribution of TP53 variants in the tumours, the authors of PMID: 33147331, conclude that these variants occur late in tumorigenesis, giving rise to the dedifferentiated component in DDCS.; Changed rating: AMBER |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.35 | TP53 |
Adrienne Flanagan gene: TP53 was added gene: TP53 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: TP53 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TP53 were set to PMID: 33147331 Phenotypes for gene: TP53 were set to Central conventional chondrosrcoma Review for gene: TP53 was set to GREEN Added comment: Inactivating mutations in TP53 are common in dedifferentiated chondrosarcoma (DDCS) and, in a subset of cases, the TP53 mutation is restricted to the dedifferentiated nonchondrogenic component (8/11, 73% of the cases tested). Half of the tumours where the conventional chondrogenic component was paired with the high-grade non-chondrogenic component showed TP53 mutation in the chondrogenic area (3/6, 50%). These findings imply that TP53 alterations occur late in tumorigenesis, potentially with a TP53-mutant subclone that progresses to the dedifferentiated component in DDCS. Identification of TP53 mutation in an otherwise low-grade central chondrosarcoma may indicate the tumor is at increased risk of dedifferentiation. Genetic testing for TP53 along with IDH1, IDH2 and TERT promoter mutations in central conventional chondrosarcoma could be useful in patient stratification. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.24 | ERI1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Tracy Lester, four patients from three different families were identified with compound heterozygous missense variants in ERI1 gene and were reported with spondyloepimetaphyseal dysplasia. In addition, another unrelated patient with a missense and a null variant was reported with spondyloepimetaphyseal dysplasia, and delayed motor milestones and speech and generalised hypotonia.; to: As reviewed by Tracy Lester, four patients from three different families were identified with compound heterozygous missense variants in ERI1 gene and were reported with spondyloepimetaphyseal dysplasia. In addition, another unrelated patient with a missense and a null variant was reported with spondyloepimetaphyseal dysplasia, and delayed motor milestones and speech and generalised hypotonia (PMID:37352860). This gene has not yet been associated with relevantly phenotypes either in OMIM or in Gene2Phenotype. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.24 | ERI1 | Achchuthan Shanmugasundram commented on gene: ERI1: As reviewed by Tracy Lester, four patients from three different families were identified with compound heterozygous missense variants in ERI1 gene and were reported with spondyloepimetaphyseal dysplasia. In addition, another unrelated patient with a missense and a null variant was reported with spondyloepimetaphyseal dysplasia, and delayed motor milestones and speech and generalised hypotonia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v4.10 | SETD5 |
Tracy Lester gene: SETD5 was added gene: SETD5 was added to Skeletal dysplasia. Sources: NHS GMS Mode of inheritance for gene: SETD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SETD5 were set to 28881385 Phenotypes for gene: SETD5 were set to Skeletal dysplasia; intellectual disability; developmental delay; facial dysmorphism Penetrance for gene: SETD5 were set to Incomplete Review for gene: SETD5 was set to GREEN Added comment: This gene is associated with an autosomal dominant neurodevelopmental disorder characterised by developmental delay, intellectual disability, and variable dysmorphic and skeletal abnormalities. Expressivity is variable and non-penetrance has been reported. As the skeletal features might appear before the ID/DD I think this gene should be added to the SD panel. We recently found a pathogenic fs in this gene in a child with short stature, short long bones and facial dysmorphism but without mention of DD/ID; however case was only 10m old at referral. Sources: NHS GMS |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.213 | NRCAM |
Sarah Leigh gene: NRCAM was added gene: NRCAM was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM. Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NRCAM were set to 35108495 Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833 Penetrance for gene: NRCAM were set to Complete |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.212 | HEATR3 |
Sarah Leigh gene: HEATR3 was added gene: HEATR3 was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber Q3_22_rating, Q3_22_MOI tags were added to gene: HEATR3. Mode of inheritance for gene: HEATR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HEATR3 were set to 35213692 Phenotypes for gene: HEATR3 were set to Anemia; Thrombocytopenia; Growth delay; Short stature; Abnormality of the skeletal system; Abnormality of finger; Abnormality of the thumb; Intellectual disability; Obesity; Abnormality of the face Penetrance for gene: HEATR3 were set to Complete |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.211 | SLC35B2 |
Sarah Leigh gene: SLC35B2 was added gene: SLC35B2 was added to Skeletal dysplasia. Sources: Literature,Expert Review Amber Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35B2 were set to 35325049 Phenotypes for gene: SLC35B2 were set to Abnormality of the skeletal system; Short long bone; Short stature; Abnormality of epiphysis morphology; Scoliosis; Multiple joint dislocation; Global develpmental delay; Intellectual disability; CNS hypomyelination; Abnormality of the corpus callosum; Cerebral atrophy; Abnormality of the amniotic fluid Penetrance for gene: SLC35B2 were set to Complete |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.190 | DVL2 |
Michael Oldridge gene: DVL2 was added gene: DVL2 was added to Skeletal dysplasia. Sources: Expert Review Mode of inheritance for gene: DVL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DVL2 were set to PMID: 35047859 Phenotypes for gene: DVL2 were set to autosomal dominant Robinow sydrome Penetrance for gene: DVL2 were set to Complete Mode of pathogenicity for gene: DVL2 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: DVL2 was set to GREEN Added comment: De novo fs variant in final exon of DVL2 identified in patient with clinical diagnosis of Robinow syndrome. This leads to a 103 residue missense tail extending beyond the WT stop codon. A number of similar fs variants have been identified in DVL1 and DVL3 leading to autosomal dominant Robinow syndrome; these variants also lead to extended missense tails and are therefore thought to act via a very specific gain of function mechanism (LOF variants in these genes do not lead to Robinow). DVL1, 2 and 3 share considerable homology (59-67%) and have overlapping function during development. Only reported in 1 case but the very specific nature of the mutation explains rareity. Should be tested as Green. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.171 | LTBP3 |
Eleanor Williams changed review comment from: This gene originally had the mode of inheritance set to monoallelic based on the Geleophysic dysplasia 3 OMIM:617809 phenotype. As Tracy Lester reports there are more than cases of patients with both a dental phenotype and short stature and so the mode of inheritance should be updated to both mono- and bi-allelic. PMID: 25899461 - Dugan et al 2015 - 2 sisters with homozygous truncating mutations (1 bp insertion) in LTBP3. Only this gene was analysed. They presented with oligodontia, short stature and mitral valve prolapse. PMID: 25669657 - Huckert et al 2015 - report 4 families (3 consanguineous) with a phenotype of significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta. WES identified homozygous or compound het protein altering variants in LTBP3 in all patients (14 bp deletion, nonsense variant, splice site variant, 2 1bp deletions). PMID:19344874 - Noor et al 2009 - consanguineous Pakistani family with oligodontia along with short stature in an autosomal-recessive fashion. A homozygous nonsense mutation, Y774X, within LTBP3 was identified. PMID: 8721563 (abstract only accessed) and PMID: 19213025 report patients with a dental and skeletal phenotype but no genetic analysis.; to: This gene originally had the mode of inheritance set to monoallelic based on the Geleophysic dysplasia 3 OMIM:617809 phenotype. This is supported by heterozygous variants in LTBP3 reported in PMID: 27068007 (McInerney-Leo et al 2016) - 2 cases with geleophysic dysplasia and 1 with acromelic dysplasia and PMID: 33082559 (Marzin et al 2021) - 2 cases with geleophysic dysplasia and 1 with acromelic dysplasia . Dental anomalies are not reported in either set of cases. As Tracy Lester reports there are more than 3 cases of patients with both a dental phenotype and short stature and so the mode of inheritance should be updated to both mono- and bi-allelic. PMID: 25899461 - Dugan et al 2015 - 2 sisters with homozygous truncating mutations (1 bp insertion) in LTBP3. Only this gene was analysed. They presented with oligodontia, short stature and mitral valve prolapse. PMID: 25669657 - Huckert et al 2015 - report 4 families (3 consanguineous) with a phenotype of significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta. WES identified homozygous or compound het protein altering variants in LTBP3 in all patients (14 bp deletion, nonsense variant, splice site variant, 2 1bp deletions). PMID:19344874 - Noor et al 2009 - consanguineous Pakistani family with oligodontia along with short stature in an autosomal-recessive fashion. A homozygous nonsense mutation, Y774X, within LTBP3 was identified. PMID: 8721563 (abstract only accessed) and PMID: 19213025 report patients with a dental and skeletal phenotype but no genetic analysis. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.171 | LTBP3 |
Eleanor Williams edited their review of gene: LTBP3: Added comment: This gene originally had the mode of inheritance set to monoallelic based on the Geleophysic dysplasia 3 OMIM:617809 phenotype. As Tracy Lester reports there are more than cases of patients with both a dental phenotype and short stature and so the mode of inheritance should be updated to both mono- and bi-allelic. PMID: 25899461 - Dugan et al 2015 - 2 sisters with homozygous truncating mutations (1 bp insertion) in LTBP3. Only this gene was analysed. They presented with oligodontia, short stature and mitral valve prolapse. PMID: 25669657 - Huckert et al 2015 - report 4 families (3 consanguineous) with a phenotype of significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta. WES identified homozygous or compound het protein altering variants in LTBP3 in all patients (14 bp deletion, nonsense variant, splice site variant, 2 1bp deletions). PMID:19344874 - Noor et al 2009 - consanguineous Pakistani family with oligodontia along with short stature in an autosomal-recessive fashion. A homozygous nonsense mutation, Y774X, within LTBP3 was identified. PMID: 8721563 (abstract only accessed) and PMID: 19213025 report patients with a dental and skeletal phenotype but no genetic analysis.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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.) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.119 | LRRK1 |
Conor Pallatt gene: LRRK1 was added gene: LRRK1 was added to Skeletal dysplasia. Sources: NHS GMS,Literature 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) Penetrance for gene: LRRK1 were set to Complete Review for gene: LRRK1 was set to GREEN Added comment: A detailed phenotypic picture of Osteosclerotic metaphyseal dysplasia (OSMD) in patients with LRRK1 variants can be seen in table 1 of Howaldt et al (2020). Lida et al (2016) identified homozygous deletion that is predicted to result in elongation of protein (p.E1980Afs*66) in a child with OSMD. Child was born to consanguineous parents, both heterozygous for variant. Guo et al (2017) identified a family with OSMD. Healthy, non-consanguineous parents have two children with OSMD that are homozygous for 1bp insertion in LRRK1 that is predicted to result in a frame-shift and produce an elongated protein (p.A1991Gfs*31) without nonsense-mediated mRNA decay. A similar effect seen in Lida et al (2016). Howaldt et al (2020) shows a patient with a homozygous splice site mutation resulting in near complete skipping of exon 3 in cDNA leading to a frameshift (p.Ala34Profs*33). The variant segregated with disorder in the family with parents being heterozygous for the variant and clinically unaffected. Miryounesi et al (2020) identified a patient with suspected OSMD from healthy, consanguineous parents. Patient is homozygous for stop gain mutation (c.2785G > T, p.E929X) in LRRK1. Parents are heterozygous for the variant. Homozygous nonsense variant in LRRK1 also identified in an individual recruited to the 100,000 genomes project for skeletal dysplasia, Osteosclerotic metaphyseal dysplasia is considered a good fit for phenotype. LRRK1 gene should be included in the skeletal dysplasia panel as a green gene at the next GMS panel update. Sources: NHS GMS, Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.100 | ARCN1 |
Andžela Lazdāne gene: ARCN1 was added gene: ARCN1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ARCN1 were set to PMID: 27476655 Phenotypes for gene: ARCN1 were set to Short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay Penetrance for gene: ARCN1 were set to Complete Review for gene: ARCN1 was set to AMBER Added comment: Clinical features like short stature, rhizomelia, laxity of the small joints, cleft palete and developmental delay also tend to occur in Skeletal dysplasia. ARCN1 gene encodes the coatomer subunit delta of COPI which is a coatomer protein complex responsible for intracellular protein transport. The importance of this mechanisms is underscored by various skeletal disorders. COPI-mediated transport is important in human development, including skeletogenesis and brain growth. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.100 | MYO18B |
Andžela Lazdāne gene: MYO18B was added gene: MYO18B was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: MYO18B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MYO18B were set to PMID: 32637634 Phenotypes for gene: MYO18B were set to Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism Penetrance for gene: MYO18B were set to Complete Review for gene: MYO18B was set to AMBER Added comment: Truncating mutations of MYO18B have been found to cause nemaline myopathy with cardiomyopathy or Klippel-Feil syndrome (KFS). Other KFS genes such as GDF3, GDF6, MEOX1, and RIPPLY2 are include in Skeletal dysplasia panel. KFS patients may have symptoms like spinal instability, disc degeneration, scoliosis, short neck, cleft palate, facial dysmorphism, and limb and hand abnormalities which may also be present in Skeletal dysplasia. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.82 | WBP11 |
Eleanor Williams gene: WBP11 was added gene: WBP11 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: WBP11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: WBP11 were set to 33276377 Phenotypes for gene: WBP11 were set to malformation syndrome affecting the cardiac, skeletal, gastrointestinal and renal systems Review for gene: WBP11 was set to GREEN Added comment: PMID: 33276377 - Martin et al 2020 - report 13 affected individuals from 7 unrelated families identified through various different cohort analysis (vertebral malformation, renal hypodysplasia, syndromic esophageal atresia, multiple congenital anomalies) in whom a WBP11 heterozygous variant is considered the top causative candidate. 5 identified variants were predicted to be protein truncating whilst the 6th was a missense variant. All variants are absent from population databases. In family 1, the variant was inherited from the apparently unaffected mother, indicating reduced penetrance, and phenotypic variance within families was observed. Phenotypes covered cardiac, vertebral, renal, craniofacial and gastrointestinal systems. At least at least 5 of the patients affected had features in three component organs so can be considered a VACTERL association. Wbp11 heterozygous null mice had vertebral and renal anomalies. Vertebral anomalies were noted in 6/13 patients from 5 families. One patient had congenital scoliosis and one abnormalities of the right upper ribs. Genomics England clinical team suggest it just meets the threshold for the skeletal dysplasia panel. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.80 | SMAD6 |
Tracy Lester gene: SMAD6 was added gene: SMAD6 was added to Skeletal dysplasia. Sources: NHS GMS Mode of inheritance for gene: SMAD6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD6 were set to 31138930 Phenotypes for gene: SMAD6 were set to Radioulnar synostosis Penetrance for gene: SMAD6 were set to Incomplete Review for gene: SMAD6 was set to GREEN Added comment: SMAD6 is frequently mutated in non-syndromic radioulnar synostosis.Using exome seq the authors found 16 LOF and 6 rare missense variants in sporadic cases, which was a highly significant association. The findings were replicated in a different cohort. Four cases had de novo variants and others were inherited in a dominant fashion. SMAD6 LOF variants have also been shown to be enriched in mid-line craniosynostosis and in certain cardiac disorders. It isn't yet clear if a variant can cause different phenotypes in the same family or combinations of these phenotypes in the same individual. Genotype-phenotype correlation is not understood. This gene is currently tested diagnostically in cases of mid-line craniosynostosis and is green on panel R100. Sources: NHS GMS |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.80 | NXN | Michael Oldridge changed review comment from: 2 unrelated families with recessive Robinow syndrome (RRS), one hom and one comp het for variants, segregation fits with recessive inheritance. Mouse model has overlapping clinical features to RRS . Gene expressed in limb bud of mice and acts in the Wnt/PCP pathway, as do the DVL genes, WNT5A and ROR2, genes also associated with the very specific RRS phenotype.; to: 2 unrelated families with recessive Robinow syndrome (RRS), one hom and one comp het for variants, segregation fits with recessive inheritance. Mouse model has overlapping clinical features to RRS . Gene expressed in limb bud of mice and acts in the Wnt/PCP pathway, as do the DVL genes, WNT5A, FZD2 and ROR2, genes also associated with the very specific RRS phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.80 | NXN | Michael Oldridge changed review comment from: 2 unrelated families with recessive Robinow syndrome (RRS), one hom and one comp het for variants, segregation fits with recessive inheritance. Mouse model has overlapping clinical features to RRS . Gene expressed in limb bud of mice and acts in the Wnt/PCP pathway, as do the DVL genes and ROR2, genes also associated with the very specific RRS phenotype.; to: 2 unrelated families with recessive Robinow syndrome (RRS), one hom and one comp het for variants, segregation fits with recessive inheritance. Mouse model has overlapping clinical features to RRS . Gene expressed in limb bud of mice and acts in the Wnt/PCP pathway, as do the DVL genes, WNT5A and ROR2, genes also associated with the very specific RRS phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.76 | RINT1 |
Eleanor Williams changed review comment from: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.; to: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. Probable association with Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities in Gene2Phenotype. PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.76 | RINT1 |
Eleanor Williams changed review comment from: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF_ and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts.; to: Associated with Infantile liver failure syndrome 3 #618641 (AR) in OMIM. PMID:31204009 - Cousin et al 2019 - describe 3 unrelated children with recurrent acute liver failure (RALF) and skeletal abnormalities who were found by WES to have compound heterozygous alterations in RINT1. All had splice alterations at the same position (c.1333+1G>A or G>T) together with a missense (p.Ala368Thr or p.Leu370Pro) or in-frame deletion (p.Val618_Lys619del). One variant was inherited from each parent. 2 of the 3 children had short stature. Imaging showed that they had abnormalities affecting the vertebrae and pelvis. Studies on patient dermal fibroblasts showed that the splice-variant results in skipping of exon 9 leading to an out-of-frame product and nonsense-mediated transcript decay and that there was decreased RINT1 protein levels, abnormal Golgi morphology, and impaired autophagic flux compared to control fibroblasts. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.70 | NPR2 |
Eleanor Williams commented on gene: NPR2: PMID: 33288834 - Simsek-Kiper et al 2020 - they investigated 26 AMDM patients from 22 unrelated families. Sanger sequencing of NPR2 was performed in 23 patients and exome sequencing was performed in 5 patients They found NPR2 variants in 23 patients (19 were homozygotes, 4 were compound heterozygotes). 22 distinct NPR2 (NM_003995) variants (14 missense, 5 nonsense, 2 intronic, and 1 single-amino acid deletion) were detected. In 14 families, segregation analysis was performed and showed the heterozygous NPR2 carrier status of the parents. Detailed radiographic evaluations were done, showing osteopenia, shortness in long tubular bones, radial bowing and radial head dislocation in the majority of cases. Other phenotypic features included motor developmental delay (11/23), global developmental delay/intellectual disability (GDD/ID) (5/23), spinal canal stenosis (2/23), and atlantoaxial dislocation (1/23), renal abnormalities and oligodontia. However, the authors note that the high level of parental consanguinity (18 patients) might have contributed to these phenotypes, from other gene variants. The height of carrier parents was also assessed and found to be significantly lower than controls. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.67 | GZF1 |
Eleanor Williams edited their review of gene: GZF1: Added comment: Associated with Joint laxity, short stature, and myopia #617662 (AR) in OMIM. As reported by Zornitza Stark, PMID: 33009817 (Zeng et al 2020) reported two Chinese sisters who presented with severe myopia, scoliosis and hearing loss. Using WES they identified two compound heterozygous variants in GZF1 (c.397400del, p. Leu133fs; c.1474del, p. Met492fs). The parents were heterozygous carriers of the variants. Functional data showed decreased levels of HA‐tagged M492fs‐GZF1 protein and no HA-tagged L133fs‐GZF1 protein or the control vector. HA‐tagged M492fs‐GZF1 protein was also localized to the cytoplasm rather than the nuclei in which wild type protein was found. This now brings the case number to 3.; Changed rating: GREEN; Changed publications: 33009817; Changed phenotypes: joint laxity, short stature, and myopia OMIM:617662, joint laxity, short stature, and myopia MONDO:0060556; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.48 | RINT1 | Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with a recommendation for a green rating following GMS review. 3 cases with compound het variants in this gene. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.33 | TONSL |
Eleanor Williams 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 32959051; 30773278; 30773277 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 v2.24 | KDELR2 |
Dmitrijs Rots gene: KDELR2 was added gene: KDELR2 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: KDELR2 were set to PMID: 33053334 Phenotypes for gene: KDELR2 were set to Increased susceptibility to fractures; joint hypermobility; Scoliosis; Bowing of the legs; Bowing of the arms Penetrance for gene: KDELR2 were set to Complete Review for gene: KDELR2 was set to GREEN Added comment: 4 families with osteogenesis imperfecta reported with functional studies reported in PMID: 33053334 Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.22 | RINT1 |
Dmitrijs Rots gene: RINT1 was added gene: RINT1 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RINT1 were set to PMID: 31204009 Phenotypes for gene: RINT1 were set to liver failure; short stature; skeletal abnormalities Penetrance for gene: RINT1 were set to Complete Review for gene: RINT1 was set to GREEN gene: RINT1 was marked as current diagnostic Added comment: Reported in 3 patients with similar phenotype in PMID: 31204009. Caused by one LoF allele and missense/in-frame hypomorphic allele. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.15 | KIAA1217 |
Eleanor Williams changed review comment from: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations. 1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency. In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Sources: Literature; to: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations. 1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency. In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Not associated with any phenotype in OMIM or Gene2Phenotype. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.14 | KIAA1217 |
Eleanor Williams gene: KIAA1217 was added gene: KIAA1217 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: KIAA1217 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KIAA1217 were set to 32369272 Phenotypes for gene: KIAA1217 were set to vertebral malformations Review for gene: KIAA1217 was set to AMBER Added comment: PMID: 32369272 - Al Dhaheri et al 2020 - 10 unrelated probands with vertebral malformations. 1 proband was compound heterozygous for variants in KIAA1217, the others were all heterozygous. 9 out of 11 variants are found in gnomad but a low allele frequency. In 3 patients (including the compound het) the variants were inherited from an unaffected parent, in the other 7 patients parental DNA was not available. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.12 | PISD |
Arina Puzriakova gene: PISD was added gene: PISD was added to Skeletal dysplasia. Sources: Literature for-review tags were added to gene: PISD. Mode of inheritance for gene: PISD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PISD were set to 31263216; 30858161; 30488656; 3561949 Phenotypes for gene: PISD were set to Liberfarb syndrome, 618889 Review for gene: PISD was set to GREEN Added comment: Associated with Liberfarb syndrome in OMIM, but not in G2P. PMID: 31263216 (2019) - In two sets of brothers from unrelated consanguineous families, sequencing revealed homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC) in the PISD gene. The patients presented with Liberfarb syndrome, characterised by skeletal dysplasia, short stature, early-onset retinal degeneration, developmental delay, microcephaly, and hearing loss. Authors noted phenotypic overlap with another previously described case (PMID: 3561949 (1986)), prompting follow-up investigation using paraffin-embedded tissue which yielded an identical homozygous variant. Haplotype analysis indicated a founder effect between all five individuals. PMID: 30858161 (2019) - Two sisters with progressive short stature, skeletal dysplasia, white matter abnormalities, congenital cataracts, sensorineural hearing loss, and mild global developmental delay, associated with compound heterozygous variants (c.830G>A and c.697+5G>A) in the PISD gene. PMID: 30488656 (2019) - Two unrelated individuals with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, as well as short stature, microcephaly, mild facial dysmorphism. Vision, hearing, and psychomotor development were reported to be normal for both patients. WES identified the same homozygous missense variant (c.797G>A) in PISD in both patients. Analysis revealed a common haplotype, which indicated remote consanguinity. Supporting functional data using patient-derived fibroblasts. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.9 | C16orf62 | Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. Two variants have been reported as compound heterozygotes in two sibs with features of 3C/Ritscher-Schinzel syndrome. Functional studies show that loss of VPS35L function results in impared autophagy and VPS35L knockout mouse resulted in early embrionic lethality (PMID 31712251). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v2.3 | NPR3 |
Ian Berry gene: NPR3 was added gene: NPR3 was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: NPR3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NPR3 were set to PMID: 30032985; 10468599 Phenotypes for gene: NPR3 were set to Tall stature; arachnodactyly; extra epiphyses; aortic dilatation Penetrance for gene: NPR3 were set to unknown Review for gene: NPR3 was set to GREEN gene: NPR3 was marked as current diagnostic Added comment: 4 individuals in 3 families reported with striking phenotypic similarity. Functional evidence compelling. Mouse model recapitulates phenotype (including skeletal features). Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.343 | Eleanor Williams Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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%. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.244 | RAD21 |
Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants: PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients with atypic Cornelia de Lange. Patient 1 - in frame deletion of exon 13 - presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features, mild 5th finger clinodactyly. This deletion was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. Patient 2 - c.592_593dup frameshift mutation - presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies (clinodactyly, syndactyly). The mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with microcephaly and classical CdLS facial features with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance. PMID: 27620904 - Martinez et al., 2017 - 92 patients recruited with syndromic intellectual disability. 1 patient identified with a variant in RAD21. A diagnosis of CdLS was made. ; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short fingers (1 patient) and thin fingers (1 patient) and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21, aswell as other genes, were reported. Other publications with patients with Cornelia de Lange and RAD21 variants but no major skeletal phenotype: PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients with atypic Cornelia de Lange. Patient 1 - in frame deletion of exon 13 - presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features, mild 5th finger clinodactyly. This deletion was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. Patient 2 - c.592_593dup frameshift mutation - presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies (clinodactyly, syndactyly). The mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with microcephaly and classical CdLS facial features with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance. PMID: 27620904 - Martinez et al., 2017 - 92 patients recruited with syndromic intellectual disability. 1 patient identified with a variant in RAD21. A diagnosis of CdLS was made. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.242 | SULF1 |
Eleanor Williams changed review comment from: Not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS. PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA. PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression. Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There is no current regions curated by ClinGen that cover these genes.; to: Not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS. PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA. PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression. Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There are no current regions curated by ClinGen that cover these genes. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.242 | TGDS |
Eleanor Williams changed review comment from: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM. PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation ; to: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM. PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation. 1 patient showed short toes, short humeri, short femora, 3 had clinodactyly V and 1 had brachymetacarpia and scoliosis. PMID: 26366375 - Pferdehirt et al 2015 - describe a 12-month-old male with molecularly confirmed Catel-Manzke syndrome who presented with Pierre Robin sequence (but without cleft palate) and hyperphalangy. This patient is on the severe end of the phenotypic spectrum, presenting with respiratory complications and failure to thrive. He has a homozygous p.Ala100Ser pathogenic variant. Both parents are heterozygous for this variant. PMID: 28422407 - Schoner et al 2017 - report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. Two compound heterozygous mutations in TGDS were found: c.298G>T; p.(Ala100Ser) and c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. Analyses of the parents’ blood DNA confirmed biparental inheritance. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.240 | TGDS |
Eleanor Williams changed review comment from: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM. PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation In 7 patients with Catel-Manzke syndrome (616145), Ehmke et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TGDS gene; to: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM. PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.230 | MANBA |
Eleanor Williams commented on gene: MANBA: Associated with Mannosidosis, beta #248510 (AR) in OMIM. No clear skeletal phenotype listed in the clinical features in OMIM. >3 cases reported with homozygous or compound het variants in OMIM. PMID: 2079835 - Kleijer et al 1990 - report a family with Mannosidosis in which a homozygous variant in the MANBA gene was later identified by Alkhayat et al. (1998). Some affected individuals showed scoliosis, one individual showed deformities of the thorax, lumbar hyperlordosis and nanism. PMID: 16401745 - Sedel et al 2006 - 1 case of boy with beta-mannosidase deficiency. No skeletal phenotype reported. PMID: 18980795 - Labauge et al 2009 - 1 case of boy with beta-mannosidase deficiency. No skeletal phenotype reported. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.226 | KAT6A |
Eleanor Williams commented on gene: KAT6A: Associated with Mental retardation, autosomal dominant 32 #616268 (AD) in OMIM. PMID: 25728777 -Tham et al 2015 - report six individuals from five unrelated families, with mutations in KAT6A detected by whole-exome sequencing. 5 different de novo heterozygous truncating mutations were identified. An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Craniosynostosis was reported in 2 families. No other major skeletal abnormalities were reported. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.220 | SULF1 |
Eleanor Williams commented on gene: SULF1: Not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS. PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA. PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression. Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There is no current regions curated by ClinGen that cover these genes. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.220 | SLCO5A1 |
Eleanor Williams commented on gene: SLCO5A1: Not associated with any phenotype in OMIM or Gene2Phenotype. PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS. PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA. PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression. Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There is no current regions curated by ClinGen that cover these genes. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.220 | RAD21 |
Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants: PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients with atypic Cornelia de Lange. Patient 1 - in frame deletion of exon 13 - presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features, mild 5th finger clinodactyly. This deletion was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. Patient 2 - c.592_593dup frameshift mutation - presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies (clinodactyly, syndactyly). The mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with microcephaly and classical CdLS facial features with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance. PMID: 27620904 - Martinez et al., 2017 - 92 patients recruited with syndromic intellectual disability. 1 patient identified with a variant in RAD21. A diagnosis of CdLS was made. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.219 | RAD21 |
Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.219 | RAD21 |
Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short and thin fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.219 | RAD21 |
Eleanor Williams changed review comment from: OMIM: - 2 cases reported in OMIM (PMID: 22633399, Deardorff et al 2012) plus 3 patients with overlapping deletions covering RAD21 (aswell as other genes). Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short and thin fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified. Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay. PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.217 | THPO |
Eleanor Williams commented on gene: THPO: Associated with Thrombocythemia 1 #187950 (AD) in OMIM. PMID: 19553636 - Graziano et al 2009 - report where the father has thrombocythemia and limb defects (absence of forearm and hand, absence of foot). Two sons had milder lower limb defects. A G185T heterozygous mutation was detected in THPO. The grandfather was found to have the variant and had thrombocythemia but no limb defect. PMID: 22453305 - Stockklausner et al 2012 - report two families with Hereditary thrombocythemia resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects in 2 out of 4 individuals with thrombocythemia (complex limb defects of the left hand in one individual, and absent proximal, middle, and distal phalanges at digits 3–5, a dysplastic proximal phalanx at digit 2 with absent middle and distal phalanx and shortened metacarpal bones at digits 3 and 4, carpal bones were partly fused to metacarpal bones at digits 2–5 in the other). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.217 | TGDS |
Eleanor Williams commented on gene: TGDS: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM. PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation In 7 patients with Catel-Manzke syndrome (616145), Ehmke et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TGDS gene |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | IFT81 |
Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype and the variant classified as a VUS. 4th case with tandem duplication of 2 exons which is predicted to result in a truncated protein. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | IFT81 |
Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly (c.1188+1G-A). The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. Only candidate gene sequencing of IFT-B complex proteins was found. A variant in IFT81 (c.2015_2019delACCGG) was also found in a second unrelated child with retinal dystrophy and intellectual disability (no skeletal phenotype) suggestive of a ciliopathy however 9 additional rare homozygous variants were found and so this variant has also been classified as a VUS in OMIM. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | IFT81 |
Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. ; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). The duplication was predicted to disrupt the ORF and cause a truncation of the peptide sequence. He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | B9D1 |
Eleanor Williams changed review comment from: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs.; to: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two unrelated patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | WDR19 |
Eleanor Williams changed review comment from: PMID: 22019273 - Bredrup et al. (2011) - 2 cases. Case 1 - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Case 2 - They also found a a Dutch patient (previously described in Vries et al, 2010) with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . 3 cases in total.; to: PMID: 22019273 - Bredrup et al. (2011) - 2 cases. Case 1 - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Case 2 - They also found a a Dutch patient (previously described in Vries et al, 2010) with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies (such as right-convex scoliosis and congenital hip dysplasia), strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . 3 cases in total. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.192 | WDR19 |
Eleanor Williams changed review comment from: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient (previously described in Vries et al, 2010) with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . 3 cases in total.; to: PMID: 22019273 - Bredrup et al. (2011) - 2 cases. Case 1 - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Case 2 - They also found a a Dutch patient (previously described in Vries et al, 2010) with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . 3 cases in total. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.168 | WDR19 |
Eleanor Williams changed review comment from: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) .; to: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient (previously described in Vries et al, 2010) with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . 3 cases in total. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.168 | WDR19 |
Eleanor Williams changed review comment from: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient with Jeune syndrome and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) .; to: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient with Jeune syndrome (asphyxiating thoracic dysplasia) and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | RBPJ | Eleanor Williams changed review comment from: PMID: 29924900 - Meester et al 2018 - analyzed a cohort comprised of 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ. They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation; to: PMID: 29924900 - Meester et al 2018 - analyzed a cohort comprised of 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ. They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. All 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | RBPJ | Eleanor Williams changed review comment from: PMID: 29924900 - Meester et al 2018 - analyzed a cohort comprised of 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ) They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation; to: PMID: 29924900 - Meester et al 2018 - analyzed a cohort comprised of 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ. They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | RBPJ | Eleanor Williams changed review comment from: PMID: 29924900 - Meester et al 2018 - analyzed cohort comprised 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ) They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation; to: PMID: 29924900 - Meester et al 2018 - analyzed a cohort comprised of 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ) They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | RBPJ | Eleanor Williams commented on gene: RBPJ: PMID: 29924900 - Meester et al 2018 - analyzed cohort comprised 194 distinct Adams–Oliver syndrome/scalp aplasia cutis congenita (ACC)/transverse terminal limb defects (TTLD) familial or sporadic cases. Most analysed using targeted next‐generation resequencing in 6 established AOS genes including RBPJ) They report 4 families in which likely heterozygous pathogenic/pathogenic variants were found in RBPJ. All were inherited in an autosomal dominant manner. 3 are novel mutations, 1 has been reported previously in another family. In all 4 families showed transverse terminal limb defects, while 3 out of 4 also were positive for scalp aplasia cutis congenita. One family also displayed microcephaly and hip dislocation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | IFT81 |
Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. Summary - 2 cases, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype; to: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. PMID: 30080953 - Pettersson et al 2018 - a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short-rib thoracic dysplasia (SRTD). He had narrow thorax, short arms, brachydactyly and short stature. Western blot analysis did not detect any wild-type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Summary - 2 cases with SNVs and strong skeletal phenotype, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype. 4th case with tandem duplication of 2 exons. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.167 | IFT81 |
Eleanor Williams commented on gene: IFT81: Associated with Short-rib thoracic dysplasia 19 with or without polydactyly (#617895) in OMIM PMID: 27666822 - Duran et al 2016 - 2 cases. Family 1 - male infant (R98-443) with features consistent with Asphyxiating thoracic dystrophy (ATD). The radiographic abnormalities included midface hypoplasia, dolichocephaly, a prominent occiput , short ribs, handlebar clavicles and short, curved appendicular bones, with the upper limbs particularly abnormally shaped. There was no polydactyly on either the hands or feet. They identified compound heterozygosity for two variants: p.Leu29Phe and p.Arg512*. Family 2 - fetus (R13-147A) suspected to have SRPS by prenatal ultrasonography. Postnatal radiographs showed dolichocephaly, a prominent occiput, midface hypoplasia, a very small thorax with shortened horizontal ribs, markedly short long bones with rounded metaphyses and marked hypoplasia of the radii, ulnae, tibiae and fibulae. Other radiographic features included small iliac bones and postaxial polydactyly of all extremities. They identified compound heterozygosity for variants in IFT81: p.Leu262 and p.Leu435del). Cultured chondrocytes from one patient showed decreased levels of transcript. Mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components PMID: 26275418 - Perrault et al 2015 - identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. The variant has been classified as a VUS in OMIM as its contribution to nephronophthisis-related ciliopathy has not be confirmed. PMID: 28460050 - Dharmat et al 2017 - Compound heterozygous mutations in IFT81 were identified in a nonsyndromic Cone rod dystrophy proband. Summary - 2 cases, one with some functional data. 3rd case with polydactyly the only skeletal component of the phenotype |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.166 | IFT52 |
Eleanor Williams changed review comment from: Associated with Short-rib thoracic dysplasia 16 with or without polydactyly (#617102) in OMIM. PMID: 26880018 - Girisha et al. 2016 - 1 case. A child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. Whole-exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52. This variant was not found in homozygous state in the 1000Genome project, the Exome Variant Server, the Exome Aggregation Consortium database, CentoMD and exome database of a local NGS service provider. The parents are heterozygous carriers. PMID: 27466190 - Zhang et al 2016 - 1 case. A non-consanguineous family with two fetuses affected by short-rib polydactyly syndrome (SRPS). Radiographic findings, taken at 20 and 23 weeks of gestation, respectively, were consistent between the two fetuses and showed undermineralized skulls, narrow thoraces with moderately shortened ribs and sharp angulations of some lower thoracic ribs, a flat appearance to the acetabular roofs, reverse campomelia of the humeri, mildly bent femurs, and no polydactyly. In one proband compound heterozygosity for two variants was found - a 1bp deletion leading to a frameshift and premature stop codon and a missense variant (c.878delT, pLeu293AlafsX21 and c.595G > A, p.Ala199Thr). One variant was inherited from each of the parents. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. PMID: 30242358 - Chen et al. 2018 - 1 case. A child from a consangiuneous family of Hui ethnicity was referred to the clinic with nystagmus and severe visual impairment since infancy also presented with severe growth retardation and mild mental retardation. She had narrow chest with short ribs and micromelic limbs. sandal gap in her right foot and dental dysplasia was also noticed. She was found to have a homozygous variation, IFT52 c.556A>G (p.T186A). This was absent in the two unaffected siblings. PMID: 31042281 - Dupont et al 2019 - report a family with compound heterogyzous variants (one missense, one causing an inframe mutation that results in less efficient splicing) in IFT52 in two foetuses in which a short rib polydactyly syndrome phenotype is described. One variant is inherited from each of the parents. One fetus also had Tortuous ureters and left pelviectasis. They also report another family in which a fetus with only a renal phenotype and a homozygous variant in IFT52 was identified.; to: Associated with Short-rib thoracic dysplasia 16 with or without polydactyly (#617102) in OMIM. PMID: 26880018 - Girisha et al. 2016 - 1 case. A child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. Whole-exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52. This variant was not found in homozygous state in the 1000Genome project, the Exome Variant Server, the Exome Aggregation Consortium database, CentoMD and exome database of a local NGS service provider. The parents are heterozygous carriers. PMID: 27466190 - Zhang et al 2016 - 1 case. A non-consanguineous family with two fetuses affected by short-rib polydactyly syndrome (SRPS). Radiographic findings, taken at 20 and 23 weeks of gestation, respectively, were consistent between the two fetuses and showed undermineralized skulls, narrow thoraces with moderately shortened ribs and sharp angulations of some lower thoracic ribs, a flat appearance to the acetabular roofs, reverse campomelia of the humeri, mildly bent femurs, and no polydactyly. In one proband compound heterozygosity for two variants was found - a 1bp deletion leading to a frameshift and premature stop codon and a missense variant (c.878delT, pLeu293AlafsX21 and c.595G > A, p.Ala199Thr). One variant was inherited from each of the parents. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. PMID: 30242358 - Chen et al. 2018 - 1 case. A child from a consangiuneous family of Hui ethnicity was referred to the clinic with nystagmus and severe visual impairment since infancy also presented with severe growth retardation and mild mental retardation. She had narrow chest with short ribs and micromelic limbs. sandal gap in her right foot and dental dysplasia was also noticed. She was found to have a homozygous variation, IFT52 c.556A>G (p.T186A). This was absent in the two unaffected siblings. PMID: 31042281 - Dupont et al 2019 - report a family with compound heterogyzous variants (one missense, one causing an inframe mutation that results in less efficient splicing) in IFT52 in two foetuses in which a short rib polydactyly syndrome phenotype is described. One variant is inherited from each of the parents. One fetus also had Tortuous ureters and left pelviectasis. They also report another family in which a fetus with only a renal phenotype and a homozygous variant in IFT52 was identified. Summary - 3 cases plus a 4th with a milder skeletal phenotype. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.166 | IFT52 |
Eleanor Williams commented on gene: IFT52: Associated with Short-rib thoracic dysplasia 16 with or without polydactyly (#617102) in OMIM. PMID: 26880018 - Girisha et al. 2016 - 1 case. A child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. Whole-exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52. This variant was not found in homozygous state in the 1000Genome project, the Exome Variant Server, the Exome Aggregation Consortium database, CentoMD and exome database of a local NGS service provider. The parents are heterozygous carriers. PMID: 27466190 - Zhang et al 2016 - 1 case. A non-consanguineous family with two fetuses affected by short-rib polydactyly syndrome (SRPS). Radiographic findings, taken at 20 and 23 weeks of gestation, respectively, were consistent between the two fetuses and showed undermineralized skulls, narrow thoraces with moderately shortened ribs and sharp angulations of some lower thoracic ribs, a flat appearance to the acetabular roofs, reverse campomelia of the humeri, mildly bent femurs, and no polydactyly. In one proband compound heterozygosity for two variants was found - a 1bp deletion leading to a frameshift and premature stop codon and a missense variant (c.878delT, pLeu293AlafsX21 and c.595G > A, p.Ala199Thr). One variant was inherited from each of the parents. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. PMID: 30242358 - Chen et al. 2018 - 1 case. A child from a consangiuneous family of Hui ethnicity was referred to the clinic with nystagmus and severe visual impairment since infancy also presented with severe growth retardation and mild mental retardation. She had narrow chest with short ribs and micromelic limbs. sandal gap in her right foot and dental dysplasia was also noticed. She was found to have a homozygous variation, IFT52 c.556A>G (p.T186A). This was absent in the two unaffected siblings. PMID: 31042281 - Dupont et al 2019 - report a family with compound heterogyzous variants (one missense, one causing an inframe mutation that results in less efficient splicing) in IFT52 in two foetuses in which a short rib polydactyly syndrome phenotype is described. One variant is inherited from each of the parents. One fetus also had Tortuous ureters and left pelviectasis. They also report another family in which a fetus with only a renal phenotype and a homozygous variant in IFT52 was identified. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.166 | B9D1 |
Eleanor Williams commented on gene: B9D1: Associated with ?Meckel syndrome 9 (#614209) and Joubert syndrome 27 (#617120) in OMIM. Gene2Phenotype reports a probable association with MECKEL SYNDROME 9. PMID: 24886560 - Romani et al 2014 - report mutations in B9D1 in two patients, a 9-year-old boy (COR363) and a 7-year-old girl (COR346), both presenting with pure JS. The mutations (cG467A; p.R156Q homo, and cA95G; p.Y32C, c.520-522delGTG; p.V175del) were inherited from heterozygous healthy parents, were not reported in public databases, and affected highly conserved residues. Missense mutations were predicted as pathogenic by prediction web tools. Neither patient showed polydactyly or orofacial features although patient COR363's facial dysmorphisms included a triangular face, retrognatism, accentuated philtrum and big ears, and patient COR346's dysmorphic facial features included frontal bossing, macrostomia, thick lips and low-set ears. PMID: 21493627 - Hopp et al 2011 - In family M456 with Meckel syndrome (MKS), a splice-donor site change in B9D1 was detected in a fetus (c.505+2T>C). Sanger sequencing revealed likely hemizygosity of this variant, with a de novo deletion of the B9D1 locus in the fetus. The deletion spans 1.713 Mb at chromosome 17p11.2, including the complete B9D1 locus. Additionally, 18 other genes were deleted. The authors also identified a novel change in a second MKS gene, CEP290. Sanger sequencing showed that the heterozygous variant, p.R2210C, was inherited from the mother. Polydactyly, that is typical in MKS, was not noted but the fetus had bilateral club feet and shortened limbs. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.159 | RAB33B |
Eleanor Williams commented on gene: RAB33B: Associated with Smith-McCort dysplasia 2 (615222) in OMIM. PMID: 22652534 - Alshammari et al. (2012) - 1 family - a consanguineous Saudi family segregating Smith-McCort syndrome. Identified a homozygous missense mutation in the RAB33B gene (K46Q). Immunoblot analysis showed severe deficiency of RAB33B in patient cells compared with control cells, and patient fibroblasts also displayed a marked reduction in the immunofluorescence signal corresponding to RAB33B but comparable signal intensity to the Golgi marker giantin. PMID: 16470731/23042644 - Neumann et al. (2006)/Dupuis et al. (2013) - 1 case. 22-year-old Turkish man with Smith-McCort syndrome-2. Identified a homozygous missense mutation in the RAB33B gene (N148K;). By Western blot analysis and immunofluorescence studies, Dupuis et al. (2013) found marked reduction of the RAB33B protein. PMID: 28127940 - Salian et al. (2017) - 3 families. 3 SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). The mutations segregated with the disorder in each family. 5 cases in total. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.155 | WDR19 |
Eleanor Williams commented on gene: WDR19: PMID: 22019273 - Bredrup et al. (2011) - sister and brother with cranioectodermal dysplasia (Sensenbrenner syndrome) identified compound heterozygosity for variants in the WDR19 gene that cosegregated with disease (L710S, and R1103X, 608151.0002). Also found a a Dutch patient with Jeune syndrome and homozygosity for a missense mutation in WDR19 (L7P). PMID: 24504730 - Fehrenbach et al 2014 - 8 year old girl with hypotonia, facial dysmorphism and retardation which were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Identified novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) . |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.153 | RAD21 |
Eleanor Williams commented on gene: RAD21: OMIM: - 2 cases reported in OMIM (PMID: 22633399, Deardorff et al 2012) plus 3 patients with overlapping deletions covering RAD21 (aswell as other genes). Other publications with patients with Cornelia de Lange and RAD21 variants PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance. PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance PMID: 27620904 - Martinez et al., 2017 - 1 patient |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.153 | COMP | Eleanor Williams Added phenotypes Epiphyseal dysplasia, multiple, 1 132400; Pseudoachondroplasia 177170 for gene: COMP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.147 | COMP | Tracy Lester reviewed gene: COMP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epiphyseal dysplasia, multiple, 1 132400, Pseudoachondroplasia 177170; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.146 | COMP | Eleanor Williams reviewed gene: COMP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.145 | COMP |
Eleanor Williams Source NHS GMS was added to COMP. Rating Changed from Green List (high evidence) to Green List (high evidence) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.138 | Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Skeletal dysplasia v1.108 | DLL4 |
Rachel Jones gene: DLL4 was added gene: DLL4 was added to Unexplained skeletal dysplasia. Sources: Other Mode of inheritance for gene: DLL4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DLL4 were set to PMID: 26299364 Phenotypes for gene: DLL4 were set to Adams-Oliver syndrome 6 616589 Penetrance for gene: DLL4 were set to Incomplete Review for gene: DLL4 was set to GREEN Added comment: Meester et al PMID: 26299364 using candidate gene approach identified 9 heterozygous mutations in DLL4 (which is a NOTCH ligand) from 91 families - same pathway as other genes previously idetified to cause Adams Oliver syndrome. No functional studies were performed, but software predicted pathogenicity of missense mutations. Evidence of non penetrance in the paper - affected siblings inheriting mutation from seemingly unaffected parent. Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||