Dataset Information

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

ABSTRACT: Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

SUBMITTER: Barat-Houari M

PROVIDER: S-EPMC5070901 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

Barat-Houari Mouna M Dumont Bruno B Fabre Aurélie A Them Frédéric Tm FT Alembik Yves Y Alessandri Jean-Luc JL Amiel Jeanne J Audebert Séverine S Baumann-Morel Clarisse C Blanchet Patricia P Bieth Eric E Brechard Marie M Busa Tiffany T Calvas Patrick P Capri Yline Y Cartault François F Chassaing Nicolas N Ciorca Vidrica V Coubes Christine C David Albert A Delezoide Anne-Lise AL Dupin-Deguine Delphine D El Chehadeh Salima S Faivre Laurence L Giuliano Fabienne F Goldenberg Alice A Isidor Bertrand B Jacquemont Marie-Line ML Julia Sophie S Kaplan Josseline J Lacombe Didier D Lebrun Marine M Marlin Sandrine S Martin-Coignard Dominique D Martinovic Jelena J Masurel Alice A Melki Judith J Mozelle-Nivoix Monique M Nguyen Karine K Odent Sylvie S Philip Nicole N Pinson Lucile L Plessis Ghislaine G Quélin Chloé C Shaeffer Elise E Sigaudy Sabine S Thauvin Christel C Till Marianne M Touraine Renaud R Vigneron Jacqueline J Baujat Geneviève G Cormier-Daire Valérie V Le Merrer Martine M Geneviève David D Touitou Isabelle I

European journal of human genetics : EJHG 20151202 7

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multi ...[more]

PMID: 26626311

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Project description:Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype-phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

Publications

The expanding spectrum of COL2A1 gene variants IN 136 patients with a skeletal dysplasia phenotype.

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