Ehlers‐Danlos/myopathy overlap syndrome caused by a large de novo deletion in COL12A1

Abstract

Autosomal dominant and recessive mutations in COL12A1 cause the Ehlers‐Danlos/myopathy overlap syndrome. Here, we describe a boy with fetal hypokinesia, severe neonatal weakness, striking hyperlaxity, high arched palate, retrognathia, club feet, and pectus excavatum. His motor development was initially delayed but muscle strength improved with time while hyperlaxity remained very severe causing recurrent joint dislocations. Using trio exome sequencing and a copy number variation (CNV) analysis tool, we identified an in‐frame de novo heterozygous deletion of the exons 45 to 54 in the COL12A1 gene. Collagen XII immunostaining on cultured skin fibroblasts demonstrated intracellular retention of collagen XII, supporting the pathogenicity of the deletion. The phenotype of our patient is slightly more severe than other cases with dominantly acting mutations, notably with the presence of fetal hypokinesia. This case highlights the importance of CNVs analysis in the COL12A1 gene in patients with a phenotype suggesting Ehlers‐Danlos/myopathy overlap syndrome.

<i>COL12A1</i> Gene Variant and a Review of the Literature: A Case Report of Ullrich Congenital Muscular Dystrophy

“…Patients with UCMD with the COL6 mutation exhibit severe muscle weakness and distal joint hyperlaxity in addition to proximal joint contractures, while relatively mild proximal and distal joint contractures are present in BM. Cases with COL12A1 gene mutations have rarely been reported in patients with UCMD-and BM-like diseases not involving COL6 mutations [2,4]. Very little is known about the spectrum of clinical symptoms deriving from mutations in collagen XII.…”

Homozygous splice site variant affecting the first von Willebrand factor A domain of COL12A1 in a patient with myopathic Ehlers‐Danlos syndrome

“…Zou et al (2014) reported three patients from two families who were found to have abnormalities in COL12A1. Subsequent reports described a total of 22 patients from 14 families who were considered to have mEDS based on the presence of abnormalities in COL12A1 and clinical features consistent with mEDS (Hicks et al, 2014;Punetha et al, 2017;Witting et al, 2018;Delbaere et al, 2020;Araújo & Antunes, 2021;Coppens et al, 2022), in accordance with the 2017 International Classification on the EDS (Malfait et al, 2017). One family (three patients) described by Hicks ac.jp/202008/downloads#variant) (Tadaka et al, 2019).…”

“…Patients 1 and 2, from the only family with autosomal recessive inheritance, were found to have a homozygous COL12A1 variant (c.7840 + 1G > A), resulting in an out‐of‐frame skipping of exon 50 and presumably resulting in protein truncation via a premature stop codon (p.Asp2567Phefs*2) (Zou et al, 2014). All variants in the autosomal dominant‐type mEDS families were localized in the region encoding the long isoform and the short isoform (Hicks et al, 2014; Zou et al, 2014; Punetha et al, 2017; Witting et al, 2018; Delbaere et al, 2020; Araújo & Antunes, 2021; Coppens et al, 2022). These variants, affecting both the long isoform and the short isoform, might cause dysfunction of collagen XII through disrupting its collagen structure.…”

“…Minor criteria include soft, doughy skin, atrophic scarring, motor developmental delay, and myopathy on muscle biopsy (Malfait et al, 2017). At present, 24 published patients from 15 families with mEDS have been reported, with 14 families showing inheritance in an autosomal dominant manner and one family in an autosomal recessive manner (Table 1) (Zou et al, 2014; Hicks et al, 2014; Punetha et al, 2017; Witting et al, 2018; Mohassel et al, 2019; Delbaere et al, 2020; Araújo & Antunes, 2021; Coppens et al, 2022).…”

The coordinated activities of collagen VI and XII in maintenance of tissue structure, function and repair: evidence for a physical interaction

“…These symptoms are frequently overlapped by features resembling Ullrich congenital muscular dystrophy, taking the form of a gradually progressive muscle disease characterized by muscle contractures, motor dysfunction, and weakness ( Hicks et al, 2014 ). This complex disease phenotype has since been referred to as myopathic-type EDS (mEDS) ( Malfait et al, 2017 ; Malek and Koster, 2021 ), associated with a range of mEDS mutations that perturb collagen XII translation, processing or secretion resulting in weakened and dysfunctional ECM that accounting for a disease phenotype of varying severity ( Araujo and Antunes, 2021 ; Malek and Koster, 2021 ; Coppens et al, 2022 ; Furuhata-Yoshimura et al, 2023 ; Izu and Birk, 2023 ; Zhu et al, 2023 ). The mEDS phenotype has been closely recapitulated in collagen XII–deficient mice ( Zhu et al, 2023 ).…”