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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 v4.48 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as red, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.45 MGP Achchuthan Shanmugasundram changed review comment from: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.; to: PMID:37923733 reported four individuals from two unrelated families with two different heterozygous MGP variants affecting Cys 19 residue (family 1: p.Cys19Phe; family 2: p.Cys19Tyr) and with previously undescribed spondyloepiphyseal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. In addition, functional evidence from heterozygous ‘knock-in’ mice expressing Cys19Phe MGP recapitulate most of the skeletal anomalies observed in the affected individuals.

Although phenotype caused by biallelic MGP variants are already reported in both OMIM (MIM #245150) and Gene2Phenotype, phenotype caused by monoallelic variants are not yet reported in either resources.
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 v4.43 IDH2 Sarah Leigh changed review comment from: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; to: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as amber, because the variants are somatic, occurring in the tumour.
Skeletal dysplasia v4.39 IDH2 Sarah Leigh edited their review of gene: IDH2: Added comment: IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.; Changed rating: GREEN
Skeletal dysplasia v4.38 NEPRO Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four unrelated cases reported with three different homozygous variants in NEPRO gene. Three unrelated cases were of Arabic/ partial Arabic descent, while the fourth case from India. The evidence available is sufficient enough to promote the rating to green in the next GMS review.
Skeletal dysplasia v4.35 NEPRO Achchuthan Shanmugasundram changed review comment from: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.; to: PMID:26633546 reported a sister and brother among 31 Saudi Arabian families studied with skeletal dysplasia and homozygous missense variant in NEPRO gene (p.Arg49Cys).

PMID:29620724 reported the same homozygous NEPRO variant (p.Arg49Cys) in two brothers of Arab descent with skeletal dysplasia. The disorder is identical to phenotypes reported in PMID:26633546 and haplotype analysis confirmed the founder nature of the variant.

PMID:31250547 reported a 13-year-old Indian girl with a different homozygous missense variant (p.Leu145Phe) and with severe short stature and skeletal dysplasia with sparse scalp hair and skin and joint laxity. Her second-cousin parents were heterozygous for the same variant.

PMID:37294112 reported a 7-year-old girl from an Arabic-speaking community in Eastern Africa with Anauxetic dysplasia 3 and another homozygous NEPRO variant (p.Arg94Cys). She was born to consanguineous parents, who reported that their shared ancestor was of Arab descent. This patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly.

This gene has been associated with relevant phenotypes in OMIM (MIM #618853), but not in Gene2Phenotype.
Skeletal dysplasia v4.32 UBA2 Eleanor Williams commented on gene: UBA2: As reviewer notes there are now additional cases reported with variants in UBA2 and skeletal defects including:

PMID: 34040189 - Schnur et al 2021 - report 16 individuals from 7 families who have variable phenotypes including Aplasia cutis congenita and skeletal defects. Ectrodyctly is present in some individuals from 4/7 families and other skeletal phenotypes such as hip abnormalities, plagiocephaly, Wormian bones, syndactyly, kyphoscoliosis, Variants were heterozygous rare variants not found in GnomAD and consist of frameshift, nonsense and missense variants.
Skeletal dysplasia v4.30 FAM111A Sarah Leigh Added comment: Comment on mode of inheritance: PMID: 34382758 reports an autosomal recessive case of Kenny-Caffey Syndrome Type 2. The proband had inherited FAM111A variants from his healthy parents (paternal heterozygous missense
variant c.976T>A (p.L326I) and maternal heterozygous
in-frame deletion variant c.1714_1716del (p.Ile572del,
rs779963813)).
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 v4.18 ERI1 Tracy Lester gene: ERI1 was added
gene: ERI1 was added to Skeletal dysplasia. Sources: NHS GMS
Mode of inheritance for gene: ERI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERI1 were set to 37352860
Phenotypes for gene: ERI1 were set to spondyloepimetaphyseal dysplasia; digital anomalies
Penetrance for gene: ERI1 were set to unknown
Mode of pathogenicity for gene: ERI1 was set to Other
Added comment: In this study, the authors uncovered a phenotypic dichotomy in eight individuals from seven unrelated families with different types of ERI1 variants and highlighted the association of missense variants with spondyloepimetaphyseal dysplasia (SEMD), which is a group of skeletal diseases characterized by anomalies in spine and long tubular bones.In contrast, the affected individuals with bi-allelic null variants showed mild intellectual disability and digital anomalies. The detailed evaluation of the skeletal phenotypes of Eri1 knockout (KO) mice and the in vitro chondrogenesis of affected-individual-derived induced pluripotent stem cells (iPSCs) supported the functional involvement of ERI1 in skeletal development. Analyses using ERI1 KO HeLa cells
and affected-individual-derived cells demonstrated functional conservation of ERI1 with its mouse ortholog in 5.8S rRNA maturation and histone mRNAs decay. The 5.8S
rRNA maturation is involved in ribosome biogenesis, defects of which are known to cause ribosomopathies characterized by skeletal dysplasia.12–15 Our study leads to the findings of an SEMD associated with ribosomopathy and established a framework for understanding the molecular mechanisms underlying the ERI1 phenotypic dichotomy.

Missense variants reported to affect residues 134,150, 155, 298 and 299. All cases with biallelic missense variants had short stature, epiphyseal, spinal and digit anomalies, as well as other variable kidney and cardiac anomalies. One case with a LOF and a missense was reported with these features and intellectual disability/developmental delay. The 3 cases with biallelic LOF variants had ID/DD, digital anomalies without the other (height varied from 8th centile to normal).
Sources: NHS GMS
Skeletal dysplasia v4.10 EN1 Eleanor Williams changed review comment from: The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model.; to: The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model. It has been additionally added to the 'Fetal anomalies' and 'Ataxia and cerebellar anomalies - narrow panel' panels based on the phenotype.

If more cases with intellectual disability/seizures are reported then it could be additionally added to those panels at that time.
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 v4.7 EN1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. One patient with a loss of function variant in this gene and a skeletal phenotype reported, plus mouse model with this gene knocked out also shows a skeletal phenotype.

A further 3 patients with 27 and 63Kb deletions 300Kb upstream of this gene also show a skeletal phenotype and this appears to be due to ablation of a long non-coding RNA loci (in mice). However, at this distance it is unlikely to be detected by the Genomics England rare disease pipeline as being associated with EN1, and there are currently no regions on Skeletal dysplasia panel covering that area of chr 2. Therefore, at the present time this gene should be rated amber, following confirmation by the clinical team.
Skeletal dysplasia v4.3 NMNAT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As two of the three reported families were distantly related, this gene should only be rated AMBER with the current evidence. However, 'watchlist' tag was added to review the rating in light of new evidence in the future.
Skeletal dysplasia v4.2 NMNAT1 Achchuthan Shanmugasundram commented on gene: NMNAT1: The 'cnv' tag was added as two of the reported cases harboured duplication variants in homozygous state and the third case harboured duplication variant together with a splicing variant.
Skeletal dysplasia v4.2 PKDCC Eleanor Williams Added comment: Comment on list classification: Further expert review from Alistair Pagnamenta supports the green rating of this gene. No change in rating needed as is green already.
Skeletal dysplasia v3.13 EXT2 Sarah Leigh changed review comment from: Biallelic EXT2 variants are also reported in Seizures, scoliosis, and macrocephaly syndrome, OMIM:616682. Table 2 in PMID: 30997052 highlights the phenotypic features of OMIM:616682. Scoliosis, which is relevant to this panel, is seen in 2/4 families reviewed in PMID: 30997052. If scoliosis is observed in more cases of OMIM:616682, then it would be appropriate to change the mode of inheritance of EXT2 to BOTH monoallelic and biallelic. The Watchlist tag has been added to this gene to reflect this situation.; to: Biallelic EXT2 variants are also reported in Seizures, scoliosis, and macrocephaly syndrome, OMIM:616682. Table 2 in PMID: 30997052 highlights the phenotypic features of OMIM:616682. Scoliosis, which is relevant to this panel, is seen in 2/4 families reviewed in PMID: 30997052. If scoliosis is observed in more cases of OMIM:616682, then it would be appropriate to change the mode of inheritance of EXT2 to BOTH monoallelic and biallelic. The Watchlist_moi tag has been added to this gene to reflect this situation.
Skeletal dysplasia v3.12 EXT2 Sarah Leigh edited their review of gene: EXT2: Added comment: Biallelic EXT2 variants are also reported in Seizures, scoliosis, and macrocephaly syndrome, OMIM:616682. Table 2 in PMID: 30997052 highlights the phenotypic features of OMIM:616682. Scoliosis, which is relevant to this panel, is seen in 2/4 families reviewed in PMID: 30997052. If scoliosis is observed in more cases of OMIM:616682, then it would be appropriate to change the mode of inheritance of EXT2 to BOTH monoallelic and biallelic. The Watchlist tag has been added to this gene to reflect this situation.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v3.12 EXT2 Sarah Leigh Added comment: Comment on phenotypes: EXT2 variants are also reported in: Seizures, scoliosis, and macrocephaly syndrome, OMIM:616682
Skeletal dysplasia v3.11 KIF5B Achchuthan Shanmugasundram commented on gene: KIF5B: PMID:36018820 reported three additional unrelated cases with autosomal dominant KIF5B variants (p.Asn255del, p.Leu498Pro and p.Leu537Pro) resulting in a clinically wide phenotypic spectrum, ranging from dilated cardiomyopathy with adult-onset ophthalmoplegia and progressive skeletal myopathy to a neurodevelopmental condition characterised by severe hypotonia with or without seizures.
Skeletal dysplasia v3.10 KIF5B Achchuthan Shanmugasundram gene: KIF5B was added
gene: KIF5B was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: KIF5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF5B were set to 35342932
Phenotypes for gene: KIF5B were set to kyphomelic dysplasia, MONDO:0008881
Review for gene: KIF5B was set to GREEN
Added comment: 4 individuals were reported with Kyphomelic dysplasia, which is characterised by severe bowing of the limbs, sharp angulation of the femora and humeri, short stature, narrow thorax, distinctive facial features, and neonatal respiratory distress. All these individuals harboured a de novo heterozygous missense variant in KIF5B gene ( two with c.272A>G (p.Lys91Arg), one with c.584C>A (p.Thr195Lys), and the other with c.701G>T(p.Gly234Val)). All three variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein.
Sources: Literature
Skeletal dysplasia v3.8 DDRGK1 Achchuthan Shanmugasundram gene: DDRGK1 was added
gene: DDRGK1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type, OMIM:602557
Review for gene: DDRGK1 was set to GREEN
Added comment: Comment on gene classification: This gene should be rated GREEN as it has been associated with Spondyloepimetaphyseal dysplasia, Shohat type from seven unrelated cases from multiple ethnicities and supported by functional studies.

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).

This gene has been associated with relevant phenotype in OMIM (MIM #602557), but not in Gene2Phenotype.
Sources: Literature
Skeletal dysplasia v3.3 GHR Arina Puzriakova Phenotypes for gene: GHR were changed from {Hypercholesterolemia, familial, modification of}, 143890; Growth hormone insensitivity; Short stature, 604271; increased responsiveness to growth hormone 604271; Increased responsiveness to growth hormone; Laron dwarfism, 262500; Proportionate Short Stature/Small for Gestational Age to Laron dwarfism, OMIM:262500; Growth hormone insensitivity, partial, OMIM:604271; Increased responsiveness to growth hormone, OMIM:604271
Skeletal dysplasia v2.223 ARSK Arina Puzriakova gene: ARSK was added
gene: ARSK was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: ARSK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSK were set to 34916232
Phenotypes for gene: ARSK were set to Mucopolysaccharidoses with short stature, coarse facial features and dysostosis multiplex
Review for gene: ARSK was set to AMBER
Added comment: Verheyen et al. 2022 (PMID: 34916232) reported four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Patients were affected with skeletal dysplasia, resembling spondyloepiphysial dysplasia. Reverse phenotyping in two individuals from one family revealed additional cardiac and ophthalmological abnormalities.
Sources: Literature
Skeletal dysplasia v2.212 MYH3 Dmitrijs Rots gene: MYH3 was added
gene: MYH3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MYH3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYH3 were set to 35169139
Review for gene: MYH3 was set to GREEN
Added comment: 17 individuals with variable vertebral and spine anomalies, as well as short stature reported in 35169139. Pathogenic variants in MYH3 cause not only Arthrogryposis.
Sources: Literature
Skeletal dysplasia v2.212 HEATR3 Sarah Leigh edited their review of gene: HEATR3: Added comment: After consultation with Helen Brittain (Clinical Fellow, Genomics England), is was concluded that there is not enough evidence for skeletal dysplasia in the cases reported in PMID: 35213692 for HEATR3 to be rated green on this panel, as the height of the affected individuals ranged from <–4 SD to normal.; Changed rating: AMBER
Skeletal dysplasia v2.209 STT3A Arina Puzriakova Added comment: Comment on list classification: Congenital disorder of glycosylation due to monoallelic variants in STT3A has been identified in at least 16 patients from 9 families (PMID: 34653363). Phenotypes included skeletal abnormalities in 10/16 subjects. Overall this supports a Green gene rating with a 'monoallelic' MOI on this panel at the next GMS panel review.
Skeletal dysplasia v2.202 DVL2 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with a recommendation for consideration for GREEN rating following GMS review. Although only 1 case has been reported, supporting evidence comes from canine data and from the fact that similar causative variants associated with Robinow syndrome have been found in the other two Dishevelled paralogs.
Skeletal dysplasia v2.199 PRKAR1A Eleanor Williams Added comment: Comment on mode of inheritance: No reports of biallelic cases found so recommendation is to change the mode of inheritance to monoallelic only after GMS review.
Skeletal dysplasia v2.195 PRKAR1A Eleanor Williams edited their review of gene: PRKAR1A: Added comment: Looking at the mode of inheritance of this gene on the Skeletal dysplasia panel where it is Both mono and bi-allelic.

In OMIM and Gene2Phenotype the relevant phenotypes of Acrodysostosis 1, with or without hormone resistance, OMIM:101800 and ACRODYSOSTOSIS respectively are listed with autosomal dominant/monoallelic inheritance.

There are several reports of heterozygous variants in PRKAR1A in patients with Acrodysostosis (PMIDs: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073). No reports of biallelic variants were found in a search of PubMed. Therefore the recommendation is for the mode of inheritance to be changed to monoallelic only.; Changed mode of pathogenicity: Other; Changed publications to: 21651393, 22464250, 22464252, 28804209, 23425300, 25075981, 26763073; Changed phenotypes to: Acrodysostosis 1, with or without hormone resistance, OMIM:101800; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
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 v2.170 LTBP3 Tracy Lester edited their review of gene: LTBP3: Added comment: Dental anomalies with short stature is recessive. Several cases reported - pathogenic variant almost missed because gene was tiered under AD mode of inheritance only.; Changed publications to: 19213025, 25899461, 25669657, 19344874, 8721563; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Set current diagnostic: yes
Skeletal dysplasia v2.169 CSNK1G1 Sarah Leigh gene: CSNK1G1 was added
gene: CSNK1G1 was added to Skeletal dysplasia. Sources: NHS GMS
Q1_22_rating tags were added to gene: CSNK1G1.
Mode of inheritance for gene: CSNK1G1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CSNK1G1 were set to 24463883; 33009664
Phenotypes for gene: CSNK1G1 were set to early-onset epileptic encephalopathy and microcephaly
Review for gene: CSNK1G1 was set to AMBER
Added comment: Not associated with relevant phenotype in OMIM and as limited evidence on Gen2Phen for association with early-onset epileptic encephalopathy and microcephaly.
NHS Genomic Medicine Service review of CSNK1G1 on the Intellectual disability panel, recommended that CSNK1G1 should be made amber / green on the skeletal dysplasia panel; as skeletal features were reported in 2/5 reported cases (PMID: 33009664)TL.
Sources: NHS GMS
Skeletal dysplasia v2.168 DSPP Michael Oldridge changed review comment from: agree should be demoted to Red.
Dentinogenesis imperfecta appears to only affect the teeth, no evidence of OI phenotype in these cases.; to: agree should be demoted to Red.
Dentinogenesis imperfecta appears to only affect the teeth, no evidence of OI phenotype in reported cases.
Skeletal dysplasia v2.162 HHAT Eleanor Williams Added comment: Comment on list classification: Promotion from grey to amber but with a recommendation for green rating following GMS review. 3 cases reported with a skeletal dysplasia phenotype and variants in HHAT.
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 v2.150 ATXN10 Arina Puzriakova Tag currently-ngs-unreportable tag was added to gene: ATXN10.
Skeletal dysplasia v2.139 TMEM251 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. 2 cases reported.
Skeletal dysplasia v2.137 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184.
Skeletal dysplasia v2.136 BMP2 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as monoallelic. OMIM also reports the biallelic phenotype of {HFE hemochromatosis, modifier of} but this is not relevant to this panel.
Skeletal dysplasia v2.130 ARCN1 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Andžela Lazdāne. ARCN1 is associated with a relevant phenotype in OMIM (MIM# 617164) which is characterised by rhizomelic short stature. At least 6 individuals from 5 unrelated families reported in literature (PMIDs: 27476655; 31075182; 33154040), which is sufficient to rate this gene as Green at the next GMS panel update.
Skeletal dysplasia v2.128 LRRK1 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. More than 3 reported cases.
Skeletal dysplasia v2.120 COPB2 Eleanor Williams gene: COPB2 was added
gene: COPB2 was added to Skeletal dysplasia. Sources: NHS GMS,Expert list,Expert Review Amber
Q3_21_rating, watchlist_moi tags were added to gene: COPB2.
Mode of inheritance for gene: COPB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COPB2 were set to 34450031; 29036432
Phenotypes for gene: COPB2 were set to juvenile osteoporosis; Osteopenia; Osteoporosis; recurrent fractures
Skeletal dysplasia v2.112 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, 615220 to {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, OMIM:615220
Skeletal dysplasia v2.111 WNT1 Ivone Leong Phenotypes for gene: WNT1 were changed from osteogenesis imperfecta; OI/osteoporosis; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221; Osteogenesis imperfecta, type XV, 615220 to {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, OMIM:615221; Osteogenesis imperfecta, type XV, 615220
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams changed review comment from: Short stature was noted in 8/8 (100%) of the patients reported in PMID:33991472; to: Short stature was noted in 8/8 (100%) and Genua vara (bow-leggedness) in 3/8 (37.5) of the patients reported in PMID:33991472
Skeletal dysplasia v2.110 LTBP1 Eleanor Williams commented on gene: LTBP1: Short stature was noted in 8/8 (100%) of the patients reported in PMID:33991472
Skeletal dysplasia v2.109 SMAD3 Eleanor Williams commented on gene: SMAD3: Note one case with a biallelic variant reported:
PMID: 32935439 - Baskin et al 2020 - first report of a LDS patient with biallelic SMAD3 variants (affecting splice site). Proband had classic Loeys-Dietz features, including dysmorphic facial features, significant scoliosis, and pectus excavatum, arachnodactyly, severe aortic root dilation, and diffuse arterial tortuosity. His parents are each heterozygous for the likely pathogenic variant and are more mildly affected.
Skeletal dysplasia v2.106 DLX5 Tracy Lester edited their review of gene: DLX5: Added comment: This gene is primarily monoallelic inheritance, many families reported. Biallelic inheritance has been rarely reported and seems to result in a more severe phenotype with deafness as well. Please update mode of inheritance to include monoallelic as well as biallelic, as a variant in this gene was almost missed because it was not in the tier 1 and 2. Thanks; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Set current diagnostic: yes
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 v2.98 LTBP1 Sarah Leigh gene: LTBP1 was added
gene: LTBP1 was added to Skeletal dysplasia. Sources: Literature
Q2_21_rating tags were added to gene: LTBP1.
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to inherited cutis laxa MONDO:0100237
Review for gene: LTBP1 was set to GREEN
Added comment: Not associated with relevant phenotype in OMIM or Gen2Phen (as of 18/05/20210). At least four terminating variants were reported in unrelated cases. Supportive in vitro and in vivo studies demonstrate the role of LTBP1 in skin and bone ECM assembly and homeostasis, in human and zebrafish (PMID 33991472).
Sources: Literature
Skeletal dysplasia v2.97 UFSP2 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974). Supportive functional studies presented for one of the variants (PMID 26428751).; to: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in unrelated cases with skeletal dysplasia (OMIM:142669 & OMIM:617974), within the UFSP2 C-terminal C78 peptidase domain, which is required for its catalytic activity. Supportive functional studies presented for one of the variants (PMID 26428751) .
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 v2.85 SCUBE3 Sarah Leigh edited their review of gene: SCUBE3: Added comment: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; Changed rating: GREEN
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 v2.75 NPR3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber with a recommendation for green rating following GMS review. 3 unrelated cases with a similar phenotype and supporting functional data and mouse model.
Skeletal dysplasia v2.73 PFN1 Eleanor Williams changed review comment from: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition.; to: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition. Wait for confirmation of this gene's involvement in Paget disease of bone in probands with different variants or that are confirmed as unrelated to the cases already described.
Skeletal dysplasia v2.72 PFN1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber. There are 3 familial cases reported but they all come from the same region of Italy and have the same variant, so possible founder effect. There is some functional data and some CNV data in addition.
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 v2.65 MBTPS1 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, but with recommendation of green rating following GMS review. 3 independent cases reported with biallelic variants in this gene and a skeletal phenotype.
Skeletal dysplasia v2.63 PLCB3 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to red. 1 case reported and some functional data showing the effect on protein levels of the variant found.
Skeletal dysplasia v2.61 ANO5 Eleanor Williams Phenotypes for gene: ANO5 were changed from Gnatodiaphyseal dysplasia; Osteogenesis Imperfecta and Decreased Bone Density; skeletal dysplasias; skeletal dysplasias; Disproportionate Short Stature to Gnathodiaphyseal dysplasia OMIM:166260; gnathodiaphyseal dysplasia MONDO:0008151; Osteogenesis Imperfecta and Decreased Bone Density; skeletal dysplasias; skeletal dysplasias; Disproportionate Short Stature
Skeletal dysplasia v2.56 UBA2 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber as there are two cases with SNVs reported.
Skeletal dysplasia v2.54 POLR1B Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber, with a recommendation for a green rating following GMS review. 5 families reported plus supportive zebrafish model.
Skeletal dysplasia v2.53 PKDCC Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to amber. 2 cases plus mouse knockout, with a similar but not exactly the same phenotype to the cases reported.
Skeletal dysplasia v2.52 MIA3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene from grey to red based on 1 family reported so far.
Skeletal dysplasia v2.45 CSGALNACT1 Eleanor Williams Added comment: Comment on list classification: Promoting from grey to amber, but with recommendation for green rating following GMS review as there are now 4 cases reported of biallelic variants in this gene in patients with mild skeletal dysplasia.
Skeletal dysplasia v2.44 CSGALNACT1 Eleanor Williams Phenotypes for gene: CSGALNACT1 were changed from Desbuquois dysplasia with mild joint laxity; non-proportionate short stature to Desbuquois dysplasia with mild joint laxity; non-proportionate short stature; Skeletal dysplasia, mild, with joint laxity and advanced bone age OMIM:618870; skeletal dysplasia, mild, with joint laxity and advanced bone age MONDO:0030029
Skeletal dysplasia v2.39 HS2ST1 Ivone Leong gene: HS2ST1 was added
gene: HS2ST1 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: HS2ST1.
Mode of inheritance for gene: HS2ST1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HS2ST1 were set to 33159882
Phenotypes for gene: HS2ST1 were set to Intellectual disability; dysmorphic features; congenital anomalies
Review for gene: HS2ST1 was set to AMBER
Added comment: This gene is not associated with a relevant phenotype in OMIM or Gene2Phenotype. Only 2 of 3 unrelated families with affected individuals described in PMID: 33159882 were reported to have ID. The affected individuals in the third family could not be assessed for ID. Other features affected individuals had were muscular hypotonia, hypoplasia/agenesis of corpus callosum, skeletal abnormalities, uni/bilateral renal agenesis (2/3) and craniofacial dysmorphism. After consulting the Genomics England Clinical Team, it was decided that this gene should be added to this panel with an Amber rating. The skeletal phenotype is relatively mild and the GMS specialist group should review whether this gene is appropriate for this panel.
Sources: Literature
Skeletal dysplasia v2.37 COG4 Ivone Leong gene: COG4 was added
gene: COG4 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: COG4.
Mode of inheritance for gene: COG4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: COG4 were set to 31949312; 30290151
Phenotypes for gene: COG4 were set to Saul-Wilson syndrome, OMIM:618150; microcephalic osteodysplastic dysplasia, Saul-Wilson type, MONDO:0019407
Mode of pathogenicity for gene: COG4 was set to Other
Review for gene: COG4 was set to AMBER
Added comment: This gene is associated with a phenotype in OMIM and Gene2Phenotype. This gene was added to the Cataracts panel by Zornitza Stark (Australian Genomics).

"Saul-Wilson syndrome (AD): 14 patients reported with DD, skeletal changes, cataracts, and growth retardation (progeriod like) All have a recurrent de novo heterozygous missense variant (p.Gly516Arg). Please note bi-allelic variants cause CDG. Sources: Expert list
Zornitza Stark (Australian Genomics), 7 Jul 2020"

PMID: 30290151 suggests that the Saul-Wilson syndrome variant is gain of function. Therefore, this gene should be considered to be Green at the next review.
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver changed review comment from: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature; to: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publication reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.36 MIA3 Aleš Maver gene: MIA3 was added
gene: MIA3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MIA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MIA3 were set to 32101163
Phenotypes for gene: MIA3 were set to short stature; skeletal dysplasia; amelogenesis
Penetrance for gene: MIA3 were set to unknown
Review for gene: MIA3 was set to RED
Added comment: The MIA3 gene is synonymous with TANGO1 in PMID:32101163. This publications reports a synonymous substitution (NM_001324062.1:c.3621A > G) that results in functionally validated exon eight skipping, leading to a truncated TANGO1/MIA3 protein. The variant was identified in four homozygous affected sibs of a consanguineous family, that presented with severe dentinogenesis imperfecta, short stature, various skeletal abnormalities, insulin-dependent diabetes mellitus, sensorineural hearing loss, and mild intellectual disability. Functional studies in HeLa and U2OS cells revealed that the truncated TANGO1/MIA3 protein is dispersed in the ER and its expression in cells with intact endogenous TANGO1/MIA3 impairs cellular collagen I secretion (PMID:32101163).
Sources: Literature
Skeletal dysplasia v2.34 HHAT Zornitza Stark gene: HHAT was added
gene: HHAT was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: HHAT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HHAT were set to 24784881; 30912300
Phenotypes for gene: HHAT were set to Nivelon-Nivelon-Mabille syndrome 600092
Review for gene: HHAT was set to AMBER
Added comment: Two unrelated families reported. Clinical features include progressive microcephaly, cerebellar vermis hypoplasia, and skeletal dysplasia. Variable features include infantile-onset seizures, dwarfism, generalized chondrodysplasia, and micromelia.
Sources: 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 v2.31 MTX2 Ivone Leong gene: MTX2 was added
gene: MTX2 was added to Skeletal dysplasia. Sources: Literature
for-review tags were added to gene: MTX2.
Mode of inheritance for gene: MTX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTX2 were set to 32917887
Phenotypes for gene: MTX2 were set to Skeletal dysplasia; Mandibuloacral dysplasia; lipodystrophy; arterial calcification
Review for gene: MTX2 was set to GREEN
Added comment: The Genomics England Clinical Team suggested that this gene should be added to this panel as there are enough skeletal features for it to be here. Therefore, this gene has been given an Amber rating and will be promoted to Green at the next review.

Review from Zornitza Stark on the Lipodystrophy - childhood onset:
"Seven individuals from 5 unrelated families reported with severe progeroid form of MAD with growth retardation, small viscerocranium with mandibular underdevelopment, distal acro-osteolyses, lipodystrophy, altered skin pigmentation, renal focal glomerulosclerosis, and extremely severe hypertension in most cases, eventually associated with disseminated arterial calcification. Loss of MTX2 in patients' primary fibroblasts led to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts were resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Sources: Literature
Zornitza Stark (Australian Genomics), 5 Oct 2020"
Sources: Literature
Skeletal dysplasia v2.30 SCUBE3 Arina Puzriakova Added comment: Comment on list classification: Rating Red as currently only one case reported with a potentially pathogenic variant associated with skeletal dysplasia. Additional cases required to corroborate causality.
Skeletal dysplasia v2.26 PRKG2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review tag). Two unrelated cases exhibiting a consistent phenotype, supported by functional characterisation of harboured variants and concordant animal models.
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 v2.20 MBTPS1 Zornitza Stark gene: MBTPS1 was added
gene: MBTPS1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: MBTPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MBTPS1 were set to 32857899; 32420688; 30046013
Phenotypes for gene: MBTPS1 were set to Skeletal dysplasia
Review for gene: MBTPS1 was set to GREEN
gene: MBTPS1 was marked as current diagnostic
Added comment: Three unrelated individuals reported with bi-allelic variants in this gene and a skeletal dysplasia, one described with SRS-like features. Elevated blood lysosomal enzymes are also a feature.
Sources: Literature
Skeletal dysplasia v2.20 PFN1 Zornitza Stark gene: PFN1 was added
gene: PFN1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PFN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PFN1 were set to 32392277; 31991009; 31346562; 32589291; 22801503
Phenotypes for gene: PFN1 were set to Paget’s disease of bone
Review for gene: PFN1 was set to AMBER
Added comment: A new phenotype association for this gene has been reported: Paget’s disease of bone (PDB).
Haploinsuffciency has been linked to PDB in 2 families with the same truncating frameshift variant (unsure if the families are related, both families are from the same region in Italy). Functional studies of this truncating variant showed abnormal protein aggregates (PMID: 32392277, 31991009). An osteoclast-specific conditional null mouse model confirmed the skeletal phenotype (PMID: 31346562). Missense variants in this gene have been previously associated with ALS (PMID: 22801503). Due to these different phenotype associations, it has been suggested that this gene can cause multisystem proteinopathy (PMID: 32589291).
Sources: Literature
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh changed review comment from: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).; to: Comment on list classification: Published reports include three variants in two cases of biallelic osteopetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identified by RNA-seq analysis of Xanthogranulomatous epithelial tumour in a patient with osteopetrosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.19 PLEKHM1 Sarah Leigh Added comment: Comment on list classification: Published reports include three variants in two cases of biallielic osteropetrosis (PMID 17404618;28290981) and three monoallelic variants in three unrelated cases (PMID 17997709;27291868), however, in one of these cases the unaffected mother of the proband also carried the PLEKHM1 variant, possibly raising the issue of penetrance (PMID 21054159). A further variant was also identifed by RNA-seq analysis of Xanthogranulomatous epithelial tumor in a patient with osteopretosis, however, the zygosity of this variant was not reported (PMID 32415263).
Skeletal dysplasia v2.15 KIAA1217 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team rating this gene amber. Although there are 10 cases reported, the mode of inheritance and level of penterance is not clear, and it would be useful to have more information prior to diagnostic use
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 v2.11 PLCB3 Zornitza Stark gene: PLCB3 was added
gene: PLCB3 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PLCB3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLCB3 were set to 29122926
Phenotypes for gene: PLCB3 were set to Spondylometaphyseal dysplasia with corneal dystrophy, MIM# 618961
Review for gene: PLCB3 was set to RED
Added comment: Single consanguineous family reported.
Sources: Literature
Skeletal dysplasia v2.11 GNPNAT1 Arina Puzriakova Added comment: Comment on list classification: Amber rating as only one family, but some supporting functional data. Additional cases required to validate pathogenicity of GNPNAT1.
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova changed review comment from: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova changed review comment from: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature; to: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation. Additional cases required to validate pathogenicity of GNPNAT1.
Sources: Literature
Skeletal dysplasia v2.10 GNPNAT1 Arina Puzriakova gene: GNPNAT1 was added
gene: GNPNAT1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: GNPNAT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GNPNAT1 were set to 32591345
Phenotypes for gene: GNPNAT1 were set to Rhizomelic skeletal dysplasia
Review for gene: GNPNAT1 was set to RED
Added comment: PMID: 32591345 (2020) - Four affected sibs from a consanguineous Pakistani family with skeletal dysplasia, characterised by severe short stature, rhizomelic shortening of the limbs, and metacarpal and metatarsal length irregularities in the hands and feet. WGS revealed a homozygous missense variant (c.226G>A; p.Glu76Lys) in GNPNAT1, which segregating with the phenotype.
Gnpnat1 gene knockdown in primary rat chondrocytes decreased cellular proliferation and expression of chondrocyte differentiation markers, indicating the importance of Gnpnat1 for growth plate chondrocyte proliferation and differentiation.
Sources: Literature
Skeletal dysplasia v2.9 PLEKHM1 Eleanor Williams commented on gene: PLEKHM1: Provisionally associated with ?Osteopetrosis, autosomal recessive 6 #611497 and Osteopetrosis, autosomal dominant 3 #618107 in OMIM.

2 biallelic and 2 monoallelic cases reported. Limited family segregation data and generally targeted sequencing of only a few candidate genes. A mouse model supports the role for this protein in bone re-absorption.

BIALLELIC

PMID: 17404618 - Van Wesenbeeck et al 2007 - report that loss of function variants in the PLEKHM1 gene are responsible for the osteopetrotic phenotype of the incisors absent (ia) rat. They then screened the coding sequence of the PLEKHM1 gene in 43 patients diagnosed with various forms of osteopetrosis and identified a patient with a homozygous G→A transition at position +1 of the donor splice site of intron 3. She was diagnosed with an autosomal-recessive intermediate form of the disease. Her parents, carriers of the mutation, were related to each other and were clinically normal. The oldest brother was heterozygous for the mutation and was clinically and radiologically normal. The youngest brother was homozygous for the mutation but had not yet developed clinical symptoms.

PMID: 28290981 - Moore et al 2017 - report 19 year old white male with history of fractures, as did 2 of his brothers, presenting with clinical osteopetrosis. Genetic testing using the CTGT Osteopetrosis NextGen sequencing panel, consisting of 13 genes associated with osteopetrosis, revealed 2 heterozygous missense mutations in PLEKHM1 (exon 4 and exon 7). No segregation data.

MONOALLELIC

PMID: 27291868 - Bo et al 2016 - report a middle‐aged Chinese man who presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in BMD. A novel de novo heterozygous mutation ( c.3051_3052delCA) in the PLEKHM1 gene was identified, after initial screening of ClCN7 and TNFSF11 genes found no disease causing variants. The patient's unaffected parents and children were also screen and were not found to have the deletion.

PMID: 17997709 - Del Fattore et al 2008 - describe a new heterozygous missense mutation (R714C) in the PLEKHM1 gene in a female Italian patient with generalized osteopenia and localized osteosclerosis, with a diagnosis of osteopetrosis of the skull, However they state that it is NOT a case of osteopetrosis, because in the patient, urine CTX, a marker of in vivo bone resorption, was normal, and in vitro assays of osteoclast formation and resorptive function showed no abnormalities. She was screened for variants only in ClC‐7 and PLEKHM1. No other family members were available for analysis.

MOUSE MODEL
PMID: 27777970 - Fujiwara et al 2016 - Plekhm1-deficient mice displayed no overt abnormalities in major organs, except for an increase in trabecular bone mass. Loss of Plekhm1 increased cancellous bone mass due to decreased bone resorption without obvious defects in other tissues and organs.
Skeletal dysplasia v2.9 SOX9 Eleanor Williams commented on gene: SOX9: ESHG2020 - Poster E-PO1.34 Ledig et al Report a case of two sisters, 46XY, who are homozygous for a variant, c.1518C>G p.(Leu506Val), in SOX9. The sisters had a suspicion of non-syndromic XY DSD (disorder of sexual development) and no signs of skeletal malformations. By luciferase assay the variant reporte dhereshowed no decrease of transactivating function on Col2a1 promotor in contrast to two SOX9 mutations (c.347C>T p.(Ala116Val) and c.358C>T p.(Arg120Cys)) known to be associated with CD. The authors suggest that SOX9 variant c.1518C>G p.(Leu506Val) is a hypomorphic mutation that causes XY DSD without raising any SOX9 related skeletal phenotype.
No publication relating to this work could be found in PubMed at this time.
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 v2.7 PKDCC Zornitza Stark gene: PKDCC was added
gene: PKDCC was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PKDCC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PKDCC were set to 30478137; 19097194
Phenotypes for gene: PKDCC were set to Rhizomelia; dysmorphism
Review for gene: PKDCC was set to AMBER
Added comment: Two unrelated consanguineous families reported with different homozygous variants
Pre-existing mouse model has similar phenotype
Sources: Literature
Skeletal dysplasia v2.6 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.6 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.5 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.5 NXN Ellen McDonagh Added comment: Comment on list classification: Two family reports and mouse model...should this be promoted to Green?
Skeletal dysplasia v2.4 NXN Ellen McDonagh changed review comment from: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Sources: Literature, Expert Review; to: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes. NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Skeletal dysplasia v2.4 NXN Ellen McDonagh gene: NXN was added
gene: NXN was added to Skeletal dysplasia. Sources: Literature,Expert Review
Mode of inheritance for gene: NXN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NXN were set to 29276006
Phenotypes for gene: NXN were set to Robinow syndrome, autosomal recessive 2 618529
Review for gene: NXN was set to AMBER
Added comment: Gene suggested by Sian Ellard (Royal Devon & Exeter NHS Foundation Trust, South West Genomic Laboratory Hub) to be added to this panel. PMID: 29276006 reports three individuals from two families with biallelic vairants in this gene that co-segregate with the disease. All three patients have typical facial characteristics of Robinow syndrome, mesomelia, brachydactyly, and broad thumbs/toes NXN knockout mice have craniofacial defects which is hypothesized to be caused by abnormal Wnt/Beta-catenin signalling.
Sources: Literature, Expert Review
Skeletal dysplasia v2.3 CSGALNACT1 Tracy Lester gene: CSGALNACT1 was added
gene: CSGALNACT1 was added to Skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: CSGALNACT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSGALNACT1 were set to 27599773; 31325655
Phenotypes for gene: CSGALNACT1 were set to Desbuquois dysplasia with mild joint laxity; non-proportionate short stature
Added comment: Desbuquois dysplasia with mild joint laxity - 2 cases reported plus a mouse model that recapitulates the phenotype: green gene for skeletal dysplasia panel
Sources: Expert Review
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 v1.340 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 v1.290 WRN Eleanor Williams changed review comment from: Comment on list classification: Keeping red for now. Associated with Werner syndrome with Osteoporosis and slender limbs listed as clinical features in OMIM. Short stature.; to: Comment on list classification: Keeping red for now. Associated with Werner syndrome with Osteoporosis and slender limbs listed as clinical features in OMIM. Short stature. But need confirmation that this is considered strong enough a skeletal dysplasia phenotype before promoting to green.
Skeletal dysplasia v1.290 WRN Eleanor Williams Added comment: Comment on list classification: Keeping red for now. Associated with Werner syndrome with Osteoporosis and slender limbs listed as clinical features in OMIM. Short stature.
Skeletal dysplasia v1.279 DPAGT1 Eleanor Williams gene: DPAGT1 was added
gene: DPAGT1 was added to Skeletal dysplasia. Sources: Expert list
Mode of inheritance for gene: DPAGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DPAGT1 were set to 12872255; 22304930
Phenotypes for gene: DPAGT1 were set to Congenital disorder of glycosylation, type Ij 608093; Myasthenic syndrome, congenital, 13, with tubular aggregates 614750; UDP-GlcNAc:Dol-P-GlcNac-P transferase deficiency (Disorders of protein N-glycosylation)
Review for gene: DPAGT1 was set to GREEN
Added comment: Adding gene to the panel from suggestion from Rhoda Akilapa. Skeletal anomalies reported including Rocker bottom feet, Bell-shaped chest, Multiple contractures, campodactily in hands,
Dorsal kyphosis, valgum feet, articular hyperlaxity (PMID: 30653653)
Sources: Expert list
Skeletal dysplasia v1.277 B3GLCT Eleanor Williams gene: B3GLCT was added
gene: B3GLCT was added to Skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: B3GLCT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GLCT were set to 16909395; 23889335
Phenotypes for gene: B3GLCT were set to Peters-plus syndrome 261540; O-fucose-specific beta-1,3-N-glucosyltransferase deficiency (Disorders of protein O-glycosylation, O-mannosylglycan synthesis deficiencies)
Review for gene: B3GLCT was set to GREEN
Added comment: Adding gene to the panel from suggestion from Rhoda Akilapa. Growth retardation, short stature, and brachydactyly reported.
Sources: Expert Review
Skeletal dysplasia v1.275 SLC35C1 Eleanor Williams gene: SLC35C1 was added
gene: SLC35C1 was added to Skeletal dysplasia. Sources: Other
Mode of inheritance for gene: SLC35C1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35C1 were set to 11326280; 12476046
Phenotypes for gene: SLC35C1 were set to Congenital disorder of glycosylation, type IIc 266265; GDP-fucose transporter deficiency (Disorders of multiple glycosylation and other glycosylation pathways)
Added comment: Adding gene to the panel from suggestion from Rhoda Akilapa. Dwarfism reported
Sources: Other
Skeletal dysplasia v1.273 SLC34A1 Eleanor Williams gene: SLC34A1 was added
gene: SLC34A1 was added to Skeletal dysplasia. Sources: Other
Mode of inheritance for gene: SLC34A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC34A1 were set to 12324554; 9560283; 25050900
Phenotypes for gene: SLC34A1 were set to Nephrolithiasis/osteoporosis, hypophosphatemic, 1, 612286
Review for gene: SLC34A1 was set to GREEN
Added comment: Adding genes that are green on the Hypophosphataemia or rickets panel
Sources: Other
Skeletal dysplasia v1.244 LMBR1 Eleanor Williams commented on gene: LMBR1: Reported microduplications in LMBR1 associated with Laurin-Sandrow syndrome are in the SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene. Duplications are >10kb and therefore the current pipeline should report these as CNVs within a green gene.
Skeletal dysplasia v1.244 RAD21 Eleanor Williams changed review comment from: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects (2 cases). ; to: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects.
Skeletal dysplasia v1.244 RAD21 Eleanor Williams changed review comment from: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects (2 cases). Other cases of deletions covering this gene and a similar phenotype are also reported.; to: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects (2 cases).
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 v1.244 SULF1 Eleanor Williams changed review comment from: Comment on list classification: Changing rating back to red. In all reported cases associated with deletions and patients with Mesomelia-synostoses syndrome both SULF1 and SLC05A1 are deleted, so better to represent this as a region.; to: Comment on list classification: Changing rating back to red. In all reported cases associated with deletions and patients with Mesomelia-synostoses syndrome both SULF1 and SLCO5A1 are deleted, so better to represent this as a region.
Skeletal dysplasia v1.244 SLCO5A1 Eleanor Williams Added comment: Comment on list classification: Changing rating back to red. In all reported cases associated with deletions and patients with Mesomelia-synostoses syndrome both SULF1 and SLCO5A1 are deleted, so better to represent this as a region
Skeletal dysplasia v1.243 SULF1 Eleanor Williams Added comment: Comment on list classification: Changing rating back to red. In all reported cases associated with deletions and patients with Mesomelia-synostoses syndrome both SULF1 and SLC05A1 are deleted, so better to represent this as a region.
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 SLCO5A1 Eleanor Williams Tag currently-ngs-unreportable was removed from gene: SLCO5A1.
Skeletal dysplasia v1.240 SULF1 Eleanor Williams Tag currently-ngs-unreportable was removed from gene: SULF1.
Skeletal dysplasia v1.240 SULF1 Eleanor Williams Added comment: Comment on list classification: Changing rating to green. Deletions covering this gene will be reported.
Skeletal dysplasia v1.239 SLCO5A1 Eleanor Williams Added comment: Comment on list classification: Changing rating to green. Deletions covering this gene will be reported.
Skeletal dysplasia v1.237 P4HB Eleanor Williams Added comment: Comment on mode of pathogenicity: 1 missense variant reported to date + deletion of several exons.
Skeletal dysplasia v1.235 MASP1 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. >3 cases reported. Skeletal phenotype.
Skeletal dysplasia v1.233 MASP1 Eleanor Williams commented on gene: MASP1: Associated with 3MC syndrome 1 #257920 (AR) in OMIM. Post natal growth retardation and radioulnar synostosis as well as craniosynostosis are listed as clinical features.

6 families and 5 variants in MASP1 reported in OMIM.

COLEC11 associated with 3MC syndrome 2 is already green on the panel.
Skeletal dysplasia v1.233 MANBA Eleanor Williams Added comment: Comment on list classification: Only 1 family reported with a strong skeletal phenotype so rating amber for now.
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 v1.230 KMT2D Eleanor Williams Added comment: Comment on list classification: Promoting from red to green as >3 cases reported and phenotype is relevant.
Skeletal dysplasia v1.228 KMT2D Eleanor Williams commented on gene: KMT2D: Associated with Kabuki syndrome 1 #147920 (AD) in OMIM. Short stature and some skeletal features (spine, hips) listed as clinical features.

> 3 cases reported in OMIM.
Skeletal dysplasia v1.228 KMT2D Eleanor Williams commented on gene: KMT2D: Associated with Kabuki syndrome 1 #147920 (AD) in OMIM. Short stature and some skeletal features (spine, hips) listed as clinical features.

> 3 cases reported in OMIM.
Skeletal dysplasia v1.228 KAT6B Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported.
Skeletal dysplasia v1.226 KAT6B Eleanor Williams commented on gene: KAT6B: Associated with Genitopatellar syndrome #606170 (AD) in OMIM. Abnormalities of the pelvis, limbs, hands and feet listed. >3 cases reported in OMIM.
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 v1.226 IGF1R Eleanor Williams commented on gene: IGF1R: Associated with Insulin-like growth factor I, resistance to #270450 (AD, AR). More than 3 cases with variants in IFG1R reported in OMIM. Clinical features include short stature due to lack of response to IGF. Clinodactyly and short hands and feet also listed.
Skeletal dysplasia v1.226 IFIH1 Eleanor Williams Added comment: Comment on list classification: 4 cases reported. All have the same gain of function variant. Genomics England clinicians confirm the phenotype is relevant.
Skeletal dysplasia v1.221 IFIH1 Eleanor Williams changed review comment from: Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .; to: Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .

PMID: 28319323 - Pettersson et al 2018 - identified the same mutation c.2465G>A p.(Arg822Gln), in IFIH1in a mother and daughter with Singleton-Merten syndrome. Patient 1 presented with congenital glaucoma, spastic paraplegia, severe dental anomalies, kyphosis, osteoporosis, recurrent infections, muscle weakness, aortic insufficiency, pericarditis, short stature, and SLE. Her mother presented with milder dental anomalies and finger deformities.
Skeletal dysplasia v1.221 IDH2 Eleanor Williams changed review comment from: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome; to: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G). Phenotypes of the patients are not given.

PMID: 24049096 - Nota et al. (2013) reported two patients with D-2-hydroxyglutaric aciduria-2, one in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo. In the other the mother also had mosacism for R140Q variant. No skeletal phenotypes are reported.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome
Skeletal dysplasia v1.221 IDH2 Eleanor Williams changed review comment from: PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.; to: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome
Skeletal dysplasia v1.221 EP300 Eleanor Williams commented on gene: EP300: Associated with Rubinstein-Taybi syndrome 2 #613684 (AD) in OMIM with Broad thumbs, Square distal fingertips, Syndactyly (in some patients) and Broad great toes listed as skeletal clinical features.

Heterozygous mutations reported in > 3 cases in OMIM.
Skeletal dysplasia v1.221 COG1 Eleanor Williams Added comment: Comment on list classification: 3 unrelated cases with plausible disease causing variants in the gene reported and a relevant phenotype.
Skeletal dysplasia v1.220 SULF1 Eleanor Williams Tag deletions tag was added to gene: SULF1.
Tag currently-ngs-unreportable tag was added to gene: SULF1.
Skeletal dysplasia v1.220 SLCO5A1 Eleanor Williams Tag deletions tag was added to gene: SLCO5A1.
Tag currently-ngs-unreportable tag was added to gene: SLCO5A1.
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 v1.220 RAD21 Eleanor Williams Added comment: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects (2 cases). Other cases of deletions covering this gene and a similar phenotype are also reported.
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 v1.219 CKAP2L Eleanor Williams commented on gene: CKAP2L: Associated with Filippi syndrome #272440 (AR) in OMIM. Mainly a digital phenotype.

PMID: 25439729 - Hussain et al 2014 - performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two children with Filippi syndrome and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs∗6), in CKAP2L which segregated with the disease in the family. They then sequenced CKAP2L in eight additional Filippi-syndrome-affected families (one from Italy, one from Poland, one from Turkey, and five from the UK) and identified five additional mutations in four of the further eight families affected by Filippi syndrome.

Sufficient cases reported, but need to assess whether the phenotype is appropriate for the skeletal dysplasia panel. It is green on the Limb disorders panel.
Skeletal dysplasia v1.219 ARID1B Eleanor Williams commented on gene: ARID1B: Associated with Coffin-Siris syndrome 1 #135900 (AD) in OMIM. Clinical features list short stature in some patients, but mainly a limb phenotype including hypoplastic digits and nails.

OMIM lists many cases of variants in ARID1B reported in patients with Coffin-Siris syndrome.
Skeletal dysplasia v1.218 THPO Eleanor Williams Added comment: Comment on list classification: Demoted from Green to red. Only two cases reported with a limb defect and no clear wider skeletal phenotype.
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 v1.216 WRN Eleanor Williams commented on gene: WRN: Associated with Werner syndrome #277700 (AR) in OMIM with Osteoporosis and slender limbs listed as clinical features.
From Genetics Home Reference "Werner syndrome is characterized by the dramatic, rapid appearance of features associated with normal aging. Individuals with this disorder typically grow and develop normally until they reach puberty. Affected teenagers usually do not have a growth spurt, resulting in short stature".

Numerous variants reported in the RECQL2/WRN gene in association with Werner syndrome in OMIM.
Skeletal dysplasia v1.214 KIAA0753 Eleanor Williams Added comment: Comment on list classification: Adding this ciliopathy gene to the skeletal dysplasia panel after consultation with the Genomics England clinical team. The reported phenotypes include skeletal dysplasias.
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 v1.206 PIK3C2A Eleanor Williams gene: PIK3C2A was added
gene: PIK3C2A was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Review for gene: PIK3C2A was set to AMBER
Added comment: Associated with Oculoskeletodental syndrome #618440 (AR) in OMIM. This is based on evidence from PMID: 31034465 - Tiosano et al 2019 - report 5 individuals from 3 unrelated consanguineous families with a similar set of clinical features including dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts. The skeletal findings included "scoliosis, delayed bone age, diminished ossification of femoral heads, cervical lordosis, shortened fifth digits with mild metaphyseal dysplasia and clinodactyly". Homozygous loss-of-function mutations in PIK3C2A were identified in each family.
Sources: Literature
Skeletal dysplasia v1.205 RPL13 Eleanor Williams changed review comment from: PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature
Skeletal dysplasia v1.205 RPL13 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to green as 4 cases, one with a missense variant but 3 with splice variants that lead to an 18 amino acid insertion in the protein have been reported.
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 v1.204 RPL13 Eleanor Williams gene: RPL13 was added
gene: RPL13 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: RPL13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPL13 were set to 31630789
Phenotypes for gene: RPL13 were set to Spondyloepimetaphyseal Dysplasia with Severe Short Stature
Review for gene: RPL13 was set to GREEN
Added comment: PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature
Skeletal dysplasia v1.202 GZF1 Eleanor Williams Added comment: Comment on list classification: Demoting from green to amber. 2 cases plus functional data, but the functional data does not strongly support a skeletal phenotype.
Skeletal dysplasia v1.198 CREB3L1 Eleanor Williams changed review comment from: Comment on list classification: Upgrading from red to green. Is Green on the Osteogenesis imperfecta panel and 4 cases reported.; to: Comment on list classification: Upgrading from red to green. Is Green on the Osteogenesis imperfecta panel and 4 cases reported.
Skeletal dysplasia v1.194 CREB3L1 Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. Is Green on the Osteogenesis imperfecta panel and 4 cases reported.
Skeletal dysplasia v1.193 CREB3L1 Eleanor Williams commented on gene: CREB3L1: 4 cases now reported each in a publication (PMID: 24079343 - whole gene deletion, PMID: 28817112 - 3bp in-frame deletion (c.934_936delAAG [p.Lys312del], PMID: 29936144 - premature stop codon c.1284C>A; p.Tyr428*, PMID: 30657919 - homozygous missense variant (p.(Ala304Val))
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 MMP9 Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM

PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family.

PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F).

PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9.

Only 2 cases reported, 3rd had variant in MMP13 not MMP9.

Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM

PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family.

PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F).

PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9.

Summary: only 2 cases reported, 3rd had variant in MMP13 not MMP9.

Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.
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 v1.191 GZF1 Eleanor Williams Added comment: Comment on list classification: Demoting from Green to Amber as a result of expert review. Only 2 cases although there is some functional evidence supporting the role of this protein in the disease.
Skeletal dysplasia v1.188 ADAMTS17 Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported with patients with short stature.
Skeletal dysplasia v1.184 RAB33B Eleanor Williams Added comment: Comment on list classification: 5 cases reported.
Skeletal dysplasia v1.183 PAM16 Eleanor Williams Added comment: Comment on list classification: 3 cases, but two are likely to share the same founder mutation. Rating amber until further cases are reported.
Skeletal dysplasia v1.182 MMP9 Eleanor Williams changed review comment from: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM

PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family.

PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F).

PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9.

Only 2 cases reported, 3rd had variant in MMP13 not MMP9.; to: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM

PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family.

PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F).

PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9.

Only 2 cases reported, 3rd had variant in MMP13 not MMP9.

Mouse model - PMID: 9590175 - Vu et al. 1998 - report that homozygous mice with a null mutation in the MMP-9/gelatinase B gene exhibit an abnormal pattern of skeletal growth plate vascularization and ossification.
Skeletal dysplasia v1.181 MMP9 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to amber as two cases have been reported with variants in this gene.
Skeletal dysplasia v1.178 MATN3 Eleanor Williams Added comment: Comment on mode of inheritance: Leaving mode of inheritance as monoallelelic, as only one case reported of biallelic variants causing Spondyloepimetaphyseal Dysplasia so far.
Skeletal dysplasia v1.177 MATN3 Eleanor Williams changed review comment from: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM.

Epiphyseal dysplasia:
PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action.
PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W).

Spondyloepimetaphyseal Dysplasia:
PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3.

Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.; to: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM.

Epiphyseal dysplasia:
PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action.
PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W).
PMID: PMID: 30080953 - Pettersson et al 2018 - in a 17‐year‐old girl born to healthy, nonconsanguineous parents of Caucasian origin who was diagnosed with multiple epiphyseal dysplasia they identified a heterozygous intragenic duplication within MATN3, affecting exons 2–5 by custom array‐CGH.

Spondyloepimetaphyseal Dysplasia:
PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3.

Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.
Skeletal dysplasia v1.177 MATN3 Eleanor Williams changed review comment from: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM.

Epiphyseal dysplasia including:
PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action.
PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W).

Spondyloepimetaphyseal Dysplasia:
PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3.

Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.; to: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM.

Epiphyseal dysplasia:
PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action.
PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W).

Spondyloepimetaphyseal Dysplasia:
PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3.

Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.
Skeletal dysplasia v1.177 MATN3 Eleanor Williams commented on gene: MATN3: Associated with Spondyloepimetaphyseal dysplasia (#608728) and Epiphyseal dysplasia, multiple, 5 (#607078) in OMIM.

Epiphyseal dysplasia including:
PMID: 11479597 - Chapman et al. 2001 - 1 family - 2 different missense mutations (V194D and R121W) identified. Suggested it might be a dominant negative mode of action.
PMID: 14729835 - Jackson et al. 2004 - in 7 families with multiple epiphyseal dysplasia they identified 4 novel mutations and 1 recurrent mutation ( R121W).

Spondyloepimetaphyseal Dysplasia:
PMID: 15121775 - Borochowitz et al. 2004 - report a large consanguineous Arab Muslim family with autosomal recessive spondyloepimetaphyseal dysplasia with a homozygous missense mutation in MATN3.

Animal studies - PMID: 16199550 - Otten et al. 2005 - mice with point mutations corresponding to human disease-causing mutations were created and found that transcripts for two of mutation were poorly expressed and protein trafficking was reduced. PMID: 16287128 - Cotterill et al. 2005 - experiments with wild type and mutant protein expressed in Chinese hamster ovaries showed intracellular retention of the mutant protein.
Skeletal dysplasia v1.176 FZD2 Eleanor Williams changed review comment from: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.

Total of 4 cases; to: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. Patient 1 has a p.Trp548* alteration previously reported. Patient 2 has missense alteration p.Gly434Val also previously reported. The phenotypes of these patients overlap with what has been previously reported, though patient 2 also presented with intellectual disability which is not typical.

Total of 4 cases
Skeletal dysplasia v1.176 FN1 Eleanor Williams Added comment: Comment on mode of pathogenicity: Only missense or inframe deletions reported to date.
Skeletal dysplasia v1.175 FN1 Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported of plausible disease causing mutations found in the FN1 gene in patients with a relevant phenotype.
Skeletal dysplasia v1.172 ADAMTS17 Eleanor Williams commented on gene: ADAMTS17: Associated with Weill-Marchesani 4 syndrome, recessive #613195 in OMIM. This condition is characterized by short stature and brachydactyly as well as eye-associated clinical features.

PMID: 19836009 - Morales et al. 2009 - 3 cases from Saudi Arabia, 2 familial and 1 sporadic. 7 affected individuals. All had short stature and ocular manifestations but not brachydactyly so are described as WMS-like. 3 different homozygous variants were detected (1 bp insertion, a splice-site mutation, and a nonsense mutation).

PMID: 22486325 - Khan et al. 2012 - 1 case. A sister and brother with WMS from a consanguineous Saudi family were found to have a 1-bp deletion that segregated with disease. The probands presented with high myopia and had spherophakia. Although both had short stature, neither had short hands, short feet, joint stiffness, or non-ocular congenital abnormalities

PMID: 24940034 - Shah et al. 2014 - 1 case. In an Indian family WES analysis identified a homozygous novel splice-site mutation c.873+1G>T in ADAMTS1 in a 21 year old proband. RT-PCR analysis in the patient showed that exon 5 was skipped, which resulted in the deletion of 28 amino acids in the ADAMTS17 protein. The proband presented with decreased vision. She had short stature, brachydactyly, but no joint stiffness.

PMID: 31019231 - Yi et al 2019 - 1 case. In a consanguineous Chinese family, a nonsense mutation c.1051 A > T in ADAMTS17 was identified. (Abstract only accessed).

More than 3 cases. Short stature reported but brachydactyly only in 1 case.
Skeletal dysplasia v1.168 ADAMTS10 Eleanor Williams commented on gene: ADAMTS10: Associated with Weill-Marchesani syndrome 1, recessive (#277600) in OMIM.

PMID: 15368195 - Dagoneau et al. 2004 - 3 cases. following homozygosity-mapping strategy in two consanguineous families from Lebanon and Saudi Arabia with Weill-Marchesani syndrome they selected ADAMTS10 for further sequencing. They found three distinct mutations of the ADAMTS10 gene in these two families and in one sporadic WMS case (one nonsense mutation (R237X) and two splice-site mutations). The variants segregated with the disease in the familial cases. All probands fulfilled the criteria for WMS with short stature, brachydactyly, limitation of joint movement, microspherophakia, dislocated lenses, severe myopia, and glaucoma.

PMID: 19836009 - Morales et al. 2009 - 2 cases. Two families which met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10 (c.1553 G > A (p.G518D) and c.2098 G > T (p.G700C)).

PMID: 30060141 - Mularczyk et al 2018 - A mouse model containing a truncation mutation on ADAMS10 seen in WMS patients was created. Homozygous WMS mice are smaller and have shorter long bones with perturbation to the zones of the developing growth plate and changes in cell proliferation.
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: 22883147 - Hassed et al. [2012] identified mutations in RBPJ through exome sequencing in two independent kindreds with autosomal dominant AOS.

PMID: 28160419 - Hassad et al 2017 - don't think they report any new families.; to: PMID: 22883147 - Hassed et al. 2012 - identified mutations in RBPJ through exome sequencing in two independent kindreds with autosomal dominant AOS.

PMID: 28160419 - Hassad et al 2017 - don't think they report any new families.
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 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 ICK Eleanor Williams commented on gene: ICK: Mouse model data

PMID: 24853502 - Moon et al 2014 - Ick null mouse embryos displayed cleft palate, hydrocephalus, polydactyly, and delayed skeletal development, closely resembling ECO syndrome phenotypes.

PMID: 24797473 - Chaya et al 2014 - ICK−/− mice died around birth probably because of respiratory failure. ICK−/− mice exhibited preaxial polydactyly in both fore and hind limbs. All four limbs were severely shortened in the ICK−/− mice at E18.5

PMID: 28380258 - Tong et al 2017 - created an Ick R272Q knock-in mouse model that recapitulates ECO pathological phenotypes. Their report focusses on the respiratory phenotype, but they report that mice displayed essential ECO pathological features such as polydactyly and shortened limbs.
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 P4HB Eleanor Williams commented on gene: P4HB: Associated with Cole-Carpenter syndrome 1 (112240) in OMIM.

PMID: 25683117 - Rauch et al. (2015) - 2 cases. 2 unrelated male patients with Cole-Carpenter syndrome-1, who exhibited multiple fractures of the long bones as well as craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features/ Identified heterozygosity for the same missense mutation in the P4HB gene ( c.1178A-G transition, Y393C) in both patients. In one the mutation occured de novo, in the other the unaffected father was mosaic for the variant.

PMID: 29384951 - Ouyang and Yang 2017 - 1 case. A 14-month-old Chinese girl presented with prominent ocular proptosis, frontal bossing, craniosynostosis, plump anterior fontanel, growth retardation, osteopenia, and distinctive facial features. Her clinical manifestation is similar to the 2 cases previously described with Cole–Carpenter syndrome-1. Whole-exome sequencing revealed a novel deletion variation in exons 5 to 8 of the P4HB gene, which was found to be heterozygous.

PMID: 30063094 - Porntaveetus et al 2018 - 1 case. First Asian CCS patient possessing the recurrent mutation in P4HB (c.1178A>G ).
Skeletal dysplasia v1.159 MMP9 Eleanor Williams commented on gene: MMP9: Associated with Metaphyseal anadysplasia 2 (613073) in OMIM

PMID: 19615667 - Lausch et al 2009 - 1 family. In a recessive kindred, family E, MMP13 was normal, but a c.21T>A transversion in exon 1 altered the start codon of MMP9, substituting methionine with lysine. The variant segregated with the disease in the family.

PMID: 28342220 - Sharony et al 2017 - 1 family. Two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses. NM_004994: c.[559C>T], p.(L187F).

PMID: 24781753 - Li et al 2015 - 0 families. 2 brothers with short stature and mixed epiphyseal and metaphyseal dysplasia. Identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T, p.(R109*). So not in MMP9.

Only 2 cases reported, 3rd had variant in MMP13 not MMP9.
Skeletal dysplasia v1.159 FZD2 Eleanor Williams commented on gene: FZD2: Associated with Omodysplasia 2 (164745) in OMIM.

PMID: 25759469 - Saal et al 2015 - 1 family. proband with omodysplasia, her unaffected parents and her affected daughter. Identified a de novo mutation (c.1644G>A, p.Trp548*) in FZD2 in the proband and her daughter that was not found in unaffected family members. Show reduced ability of this mutant form of FZD2 to interact with its downstream target DISHEVELLED. Furthermore, expressing the mutant form of FZD2 in vitro is not able to facilitate the cellular response to canonical Wnt signaling like wild-type FZD2.

PMID: 29230162 - Türkmen et al 2017 - 1 patient. A heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits.

PMID: 29383830 - invalid pubmed id

PMID: 29383834 - Nagasaki et al 2018 - 1 patient. 16-year-old boy with OMOD2 or Robinow syndrome-like phenotype. Molecular analysis identified a de novo, heterozygous, nonsense mutation (c.1640C>A, p.S547*) in FZD2.

PMID: 30455931 - Warren et al 2018 - 2 patients. Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical.
Skeletal dysplasia v1.155 XYLT2 Eleanor Williams commented on gene: XYLT2: PMID: 26027496 - Munns et al 2015 - 3 patients from 2 unrelated families with bone fragility, hearing impairment, cardiac septal defects, and learning difficulties (spondyloocular syndrome). Identified homozygosity for a 1-bp duplication and a 1-bp deletion, respectively. The mutations, which segregated with disease in each family, were not found in public variant databases.

PMID: 26987875- Taylan et al 2016 - report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2.
Skeletal dysplasia v1.155 RBPJ Eleanor Williams commented on gene: RBPJ: PMID: 22883147 - Hassed et al. [2012] identified mutations in RBPJ through exome sequencing in two independent kindreds with autosomal dominant AOS.

PMID: 28160419 - Hassad et al 2017 - don't think they report any new families.
Skeletal dysplasia v1.154 IDH2 Eleanor Williams commented on gene: IDH2: PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.
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 DDR2 Eleanor Williams Added phenotypes Spondylometaepiphyseal dysplasia, short limb-hand type 271665, at least 3 cases reported for gene: DDR2
Skeletal dysplasia v1.153 WNT1 Eleanor Williams Added phenotypes osteogenesis imperfecta; OI/osteoporosis; {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221; Osteogenesis imperfecta, type XV, 615220 for gene: WNT1
Skeletal dysplasia v1.153 SERPINF1 Eleanor Williams Added phenotypes Osteogenesis imperfecta, type VI, 613982; osteogenesis imperfecta; OI/osteoporosis; Osteogenesis Imperfecta, Recessive for gene: SERPINF1
Skeletal dysplasia v1.153 LRP5 Eleanor Williams Added phenotypes [Bone mineral density variability 1] 601884; Osteopetrosis, autosomal dominant 1 607634; Osteosclerosis 144750; van Buchem disease, type 2 607636; Osteoporosis-pseudoglioma syndrome 259770; Hyperostosis, endosteal 144750; {Osteoporosis} 166710 for gene: LRP5
Skeletal dysplasia v1.153 ANO5 Eleanor Williams Added phenotypes Gnatodiaphyseal dysplasia; Osteogenesis Imperfecta and Decreased Bone Density; skeletal dysplasias; Disproportionate Short Stature for gene: ANO5
Skeletal dysplasia v1.153 PLS3 Eleanor Williams Added phenotypes Bone mineral density QTL18, osteoporosis 300910 for gene: PLS3
Skeletal dysplasia v1.153 POR Eleanor Williams Added phenotypes Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750; Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571 for gene: POR
Skeletal dysplasia v1.147 WNT1 Tracy Lester reviewed gene: WNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: OI/osteoporosis, Osteogenesis imperfecta, type XV, 615220, {Osteoporosis, early-onset, susceptibility to, autosomal dominant}, 615221, osteogenesis imperfecta; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Skeletal dysplasia v1.147 SERPINF1 Tracy Lester reviewed gene: SERPINF1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: OI/osteoporosis, Osteogenesis imperfecta, type VI, 613982, Osteogenesis Imperfecta, Recessive, osteogenesis imperfecta; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.147 POR Tracy Lester reviewed gene: POR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis 201750, Disordered steroidogenesis due to cytochrome P450 oxidoreductase 613571; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Skeletal dysplasia v1.147 PLS3 Tracy Lester reviewed gene: PLS3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Bone mineral density QTL18, osteoporosis 300910; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Skeletal dysplasia v1.147 LRP5 Tracy Lester reviewed gene: LRP5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperostosis, endosteal 144750, Osteopetrosis, autosomal dominant 1 607634, Osteoporosis-pseudoglioma syndrome 259770, Osteosclerosis 144750, van Buchem disease, type 2 607636, [Bone mineral density variability 1] 601884, {Osteoporosis} 166710; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Skeletal dysplasia v1.147 DDR2 Tracy Lester reviewed gene: DDR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spondylometaepiphyseal dysplasia, short limb-hand type 271665, at least 3 cases reported; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.147 ANO5 Tracy Lester reviewed gene: ANO5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Gnatodiaphyseal dysplasia, Osteogenesis Imperfecta and Decreased Bone Density, skeletal dysplasias, Disproportionate Short Stature; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.146 POR Eleanor Williams reviewed gene: POR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Skeletal dysplasia v1.145 POR Eleanor Williams Source NHS GMS was added to POR.
Rating Changed from Green List (high evidence) to Green List (high evidence)
Skeletal dysplasia v1.139 TRPV6 Helen Brittain gene: TRPV6 was added
gene: TRPV6 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TRPV6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPV6 were set to 29861107
Phenotypes for gene: TRPV6 were set to Hyperparathyroidism, transient neonatal, 618188
Penetrance for gene: TRPV6 were set to unknown
Review for gene: TRPV6 was set to GREEN
Added comment: 6 unrelated children with skeletal abnormalities detected in the third trimester of pregnancy, who presented at birth with elevated serum PTH and alkaline phosphatase activity, with normal or low ionized calcium. Skeletal anomalies included generalized osteopenia, narrow chest, short ribs with multiple healing fractures, and bowing or fractures of long bones. All affected individuals experienced postnatal respiratory difficulties requiring ventilatory support in the first few weeks to months of life. In addition, most showed poor feeding, with some requiring tube feeding.
Sources: Literature
Skeletal dysplasia v1.131 ABL1 Rebecca Foulger gene: ABL1 was added
gene: ABL1 was added to Skeletal dysplasia. Sources: Literature
missense tags were added to gene: ABL1.
Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ABL1 were set to 28288113
Phenotypes for gene: ABL1 were set to Congenital heart defects and skeletal malformations syndrome, 617602
Mode of pathogenicity for gene: ABL1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: Added to Skeletal dysplasia panel with Amber rating as suggested by Helen Brittain. Wang et al, 2017 (PMID:28288113) report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities and failure to thrive. They report 2 variants in 4 families (6 individuals). Helen Brittain, clinical fellow, notes that: "the broader skeletal manifestations (scoliosis / pectus) are classically thought of as part of the Marfan / FTAAD spectrum rather than a skeletal dysplasia. Therefore do not think that skeletal dysplasia (or limb panel) would be the primary route for diagnosis here and would opt for amber on the basis that we need to see the phenotype across other cases first."
Sources: Literature
Skeletal dysplasia v1.127 SLC10A7 Ellen McDonagh gene: SLC10A7 was added
gene: SLC10A7 was added to Unexplained skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: SLC10A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC10A7 were set to 30082715
Phenotypes for gene: SLC10A7 were set to skeletal dysplasia and amelogenesis imperfecta
Added comment: PMID: 30082715 reports five different SLC10A7 variants in four patients from four unrelated families and two patients from two distantly related families. The study states that the variants segregated according to a recessive mode of inheritance, however the genotype was not shown on the pedigree diagram. Further evidence was provided in a knockout mouse model that displayed abnormal development of skeletal structures and teeth anomalies.
Sources: Literature
Skeletal dysplasia v1.122 BMP2 Eleanor Williams commented on gene: BMP2: More than 3 families/cases reported in PMID: 29198724 for monoallelic variants in this gene and Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies.
Skeletal dysplasia v1.121 BMP2 Eleanor Williams Added comment: Comment on list classification: Rating green based on publication (PMID: 29198724) reporting sufficient cases associated with a relevant phenotype. Rating has been checked with Genomics England clinical team.
Skeletal dysplasia v1.120 CCDC8 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Sufficient unrelated cases and more than one causative variant, and variants in this gene are currently reported in an external diagnostic lab
Skeletal dysplasia v1.118 CCDC8 Louise Daugherty Added comment: Comment on publications: added publication to support gene-disease
Skeletal dysplasia v1.115 SMOC1 Eleanor Williams gene: SMOC1 was added
gene: SMOC1 was added to Unexplained skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: SMOC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMOC1 were set to 21194678; 21194680
Phenotypes for gene: SMOC1 were set to Ophthalmo-acromelic syndrome; Microphthalmia with limb anomalies 206920; Polydactyly
Review for gene: SMOC1 was set to GREEN
Added comment: Sourced from Genetic Home Reference. >3 cases/family reports for homozygous loss of function variants in this gene, in affacted individuals with microphthalmia with limb anomalies (see publications). This is a confirmed DD gene for OPHTHALMOACROMELIC SYNDROME. HPO terms from Gene2Phenotype include
Camptodactyly of 2nd-5th fingers, Foot oligodactyly, Hand oligodactyly, Postaxial foot polydactyly, Postaxial hand polydactyly, Toe syndactyly.
Sources: Expert Review
Skeletal dysplasia v1.114 NOTCH1 Eleanor Williams gene: NOTCH1 was added
gene: NOTCH1 was added to Unexplained skeletal dysplasia. Sources: Expert Review
Mode of inheritance for gene: NOTCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NOTCH1 were set to 25132448; 25963545; 27077170; 25132448
Phenotypes for gene: NOTCH1 were set to Adams-Oliver syndrome 5, 616028; Combination of aplasia cutis congenita of the scalp vertex and terminal transverse limb defects (e.g., amputations, syndactyly, brachydactyly, or oligodactyly); AOS; Limb, scalp and skull defects
Review for gene: NOTCH1 was set to GREEN
Added comment: There are more than three unrelated cases reported for variants in NOTCH1 causing Adams-Oliver type 5 syndrome
Sources: Expert Review