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.

Integrated analysis of COL2A1 variant data and classification of type II collagenopathies

“…The average age at diagnosis was 5.89 years, and the sex ratio was nearly equal. Among the 18 cases of SEMD‐S collected in this review, 14 substitutions were found; c.3121G > A (p.Gly1041Ser) was reported twice …”

“…Interestingly, 49 Gly substitutions occurred in the 50 missense cases, suggesting the decisive role of glycine (references are shown in Supplementary Table S1). Two intronic variants (c.2094 + 1G > A, c.2353 + 4_2353 + 7del) and two cases of gene deletion (c.2745_3221del, c.2449_2466del) also caused ACG 2 …”

“…In an unusual case reported by Wubben et al, two mutation types (substitution and small deletion) occurred in one patient . For the cases of deletion mutations, we collected 125 and 8 small and large deletions, respectively, including five cases of COL2A1 gene deletions which occurred in patients with STL 1 …”

“…Although SMD‐S is usually caused by mutation in the fibronectin 1 gene, in 2017, Machol et al reported two cases with concurrent SMD‐corner fracture type with different heterozygous COL2A1 pathogenic variants (p.Gly345Asp; p.Gly945Ser) . Notably, p.Gly345Asp was previously described in a clinical case of SEMD‐S, and their significant clinical similarities suggested an overlap between SMD corner fracture and SEMD‐S …”

Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia

“…Autosomal dominant mutations in COL1A1 are known causes of Ehlers-Danlos syndrome and osteoporosis (Steiner et al 1993;Byers 2000). Similarly, autosomal dominant mutations in COL2A1 are responsible for a number of osteochondrodysplasias (Barat-Houari et al 2016), and mutations in both COL2A1 and TRIP11 are implicated in Type 2 and Type 1A achondrogenesis, respectively. KMT2D mutations are known to be associated with Kabuki syndrome, which is characterized by cranial and facial malformations, growth deficiency, short stature, and skeletal malformations.…”