Biallelic variants p.Arg1133Cys and p.Arg1379Cys in <i>COL2A1</i>: Further delineation of phenotypic spectrum of recessive Type 2 collagenopathies

Girisha, Katta M.; Shah, Hitesh; Moirangthem, Amita; Shukla, Anju; Kim, Ok Hwa; Nishimura, Gen

doi:10.1002/ajmg.a.61414

Cited by 7 publications

(9 citation statements)

References 14 publications

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“…Patients with mutations in the C-terminal region present with milder phenotypes with some characteristic symptoms, probably because the variant has limited influence on the mature type II collagen [ 11 ]. Brachydactyly, especially of the middle and distal phalanges, seems to be the most common clinical feature of variants in the C‐terminal region [ 3 , 12 ], which was also observed in the present case. Further, variants in the C-terminal propeptide are also associated with platyspondylic skeletal dysplasia Torrance type(MIM#151210) and with Spondyloperipheral dysplasia (SPPD, MIM#271700) [ 13 ].…”

Section: Discussionsupporting

confidence: 80%

“…This was supported by Barat‐Houari et al [ 4 ], who described a more severe patient with SEDC with homozygosity. However, Girisha et al [ 3 ] then reported four patients with bi-allelic variants in COL2A1 which rarely caused SEDC. In type II collagenopathies dominantly inherited, more than 100 COL2A1 variants have been reported in patients diagnosed with SEDC, and most of the variants are located in the triple-helical domain (74% Gly replacements and 10% Arg-to-Cys substitutions) [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Type II collagenopathies are resulted by mutation of COL2A1 (MIM #120140) and are inherited in an autosomal dominant manner. Recently, autosomal recessive inherence was identified in patients with type II collagenopathies: all of the patients were from West Asia [ 3 – 6 ], probably owing to a higher rate of consanguinity and extensive development of gene sequencing.…”

Section: Introductionmentioning

confidence: 99%

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A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report

Zhang

Yao

et al. 2021

BMC Med Genomics

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Background Type II collagenopathies are a spectrum of diseases and skeletal dysplasia is one of the prominent features of collagenopathies. Molecular defects of the COL2A1 gene cause type II collagenopathies that is mainly an autosomal dominant disease, whereas some rare cases with autosomal recessive inheritance of mode have also been identified. Case presentation The patient was a 5-year-old male with a short neck, flat face, epiphyseal dysplasia, irregular vertebral endplates, and osteochondritis. Sequencing result indicated NM_001844.4: c.3662C > T; p. (Ser1221Phe) a novel missense variant, leading to a serine-to-phenylalanine substitution. Sanger sequencing confirmed the variant compared to his parents and brother. Conclusions We identified a novel homozygous variant of the COL2A1 gene as the cause of type II collagenopathies in a Chinese male, enriching the spectrum of genotypes. This is the first case of type II collagenopathies inherited in an autosomal recessive manner in China and East Asia, and it is the first case that resulted from serine substitution in the world.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report

Zhang

Yao

et al. 2021

BMC Med Genomics

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“…Rare variants were retrieved with minor allele frequency of < 1% in population databases [Exome Aggregation Consortium (ExAC) and gnomAD 54,55 ] and our in-house data. Variants were prioritized for the phenotypes 56 .…”

Section: Molecular Genetic Analysis Genomicmentioning

confidence: 99%

Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing

Nayak

Schneeberger

Patil

et al. 2021

Sci Rep

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Marfan syndrome and related disorders are a group of heritable connective tissue disorders and share many clinical features that involve cardiovascular, skeletal, craniofacial, ocular, and cutaneous abnormalities. The majority of affected individuals have aortopathies associated with early mortality and morbidity. Implementation of targeted gene panel next-generation sequencing in these individuals is a powerful tool to obtain a genetic diagnosis. Here, we report on clinical and genetic spectrum of 53 families from India with a total of 83 patients who had a clinical diagnosis suggestive of Marfan syndrome or related disorders. We obtained a molecular diagnosis in 45/53 (85%) index patients, in which 36/53 (68%) had rare variants in FBN1 (Marfan syndrome; 63 patients in total), seven (13.3%) in TGFBR1/TGFBR2 (Loeys–Dietz syndrome; nine patients in total) and two patients (3.7%) in SKI (Shprintzen–Goldberg syndrome). 21 of 41 rare variants (51.2%) were novel. We did not detect a disease-associated variant in 8 (15%) index patients, and none of them met the Ghent Marfan diagnostic criteria. We found the homozygous FBN1 variant p.(Arg954His) in a boy with typical features of Marfan syndrome. Our study is the first reporting on the spectrum of variants in FBN1, TGFBR1, TGFBR2, and SKI in Indian individuals.

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“…To date, no clear genotype–phenotype correlations have been obtained in type II collagenopathies, which is most likely associated with the existence of the inter- and intrafamilial variability of clinical manifestations, differences in the specificity of clinical manifestations in patients with the same pathogenic variants, age-related evolution of phenotypes, and evidence of marked genetic heterogeneity due to some cases with an autosomal recessive type of inheritance [ 13 , 15 , 23 , 24 , 25 , 26 ]. Nevertheless, conducting a clinical and genetic analysis of various nosological variants of the skeletal collagenopathies spectrum can improve our understanding of the pathogenetic mechanisms and more accurately predict their course at the early stages, improving an individual’s medical care and quality of life [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I

Маркова

Kenis²,

Melchenko³

et al. 2022

Genes

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The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.

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Biallelic variants p.Arg1133Cys and p.Arg1379Cys in COL2A1: Further delineation of phenotypic spectrum of recessive Type 2 collagenopathies

Cited by 7 publications

References 14 publications

A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report

A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report

Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing

Clinical and Genetic Characteristics of COL2A1-Associated Skeletal Dysplasias in 60 Russian Patients: Part I

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