Genetic variations and clinical spectrum of dystroglycanopathy in a large cohort of Chinese patients

Abstract

Dystroglycanopathy is a group of muscular dystrophies with deficient glycosylation of alpha‐dystroglycan (α‐DG). We recruited patients from 36 tertiary academic hospitals in China. In total, 143 patients with genetically diagnosed dystroglycanopathy were enrolled. Of these, limb girdle muscular dystrophy was the most common initial diagnosis (83 patients) and Walker‐Warburg syndrome was the least common (1 patient). In 143 patients, mutations in FKRP gene were the most prevalent (62 patients), followed by POMT2, POMT1 (16), POMGNT1, ISPD (14), FKTN, GMPPB, B3GALNT2, DPM3, and DAG1. Several frequent mutations were identified in FKRP, POMT1, POMGNT1, ISPD, and FKTN genes. Many of these were founder mutations. Patients with FKRP mutations tended to have milder phenotypes, while those with mutations in POMGNT1 genes had more severe phenotypes. Mental retardation was a clinical feature associated with mutations of POMT1 gene. Detailed clinical data of 83 patients followed up in Peking University First Hospital were further analyzed. Our clinical and genetic analysis of a large cohort of Chinese patients with dystroglycanopathy expanded the genotype variation and clinical spectrum of congenital muscular dystrophies.

Clinical exome sequencing identifies novel compound heterozygous mutations of the POMT2 gene in patients with limb‐girdle muscular dystrophy

“…The phenotypic manifestations of POMT2 gene mutations are ranging from severe phenotypes, such as WWS or Fukuyama CMD, through MEB‐like disease, to the relatively mild LGMD2N (Biancheri et al, 2007; Mercuri et al, 2006; Murakami et al, 2009). To date, 16 studies have identified 52 cases with mild LGMD, which caused by different POMT2 mutations including 10 homozygous mutations and 34 compound heterozygous mutations (Biancheri et al, 2007; Brun et al, 2018; Chen et al, 2021; Gan et al, 2021; Godfrey et al, 2007; Hafner et al, 2014; Johnson et al, 2018; Kuhn et al, 2016; Mahjoub et al, 2020; Murakami et al, 2009; Ostergaard et al, 2018; Punetha et al, 2016; Saredi et al, 2014; Song et al, 2021; Tomita et al, 2021; Yildirim et al, 2021) (Case 1–Case 52) (Table 3). Here, we report novel compound heterozygous mutations of POMT2 , which further expand the mutation spectrum of POMT2 .…”

“…The dystroglycanopathies are a group of genetically heterogeneous congenital muscular dystrophy (CMD), which characterized by variable neurological and ocular involvement (Song et al, 2021). The phenotypic manifestations of protein O‐mannosyltransferase 2 ( POMT2 ) gene mutations have emerged as being rather broad, ranging from severe phenotypes such as Walker–Warburg syndrome (WWS) or Fukuyama CMD, through muscle‐eye‐brain (MEB)‐like disease, to the relatively mild limb‐girdle muscular dystrophy type 2N (LGMD2N), which characterized by wasting and weakness of the muscles of the shoulder and hip region (Biancheri et al, 2007; Mercuri et al, 2006; Murakami et al, 2009).…”

Phenotype and Genotype Study of Chinese POMT2-Related α-Dystroglycanopathy

“…The inclusion criteria for α-DGP were described in our previous study ( Song et al, 2020 ). In this study, patients with molecular genetic results indicating POMT2 variants were enrolled, and patients diagnosed with other types of CMD or with other gene variants were excluded.…”

Uniparental disomy for chromosome 1 with POMGNT1 splice-site variant causes muscle-eye-brain disease

“…Dystroglycanopathy (DGP) is a group of autosomal recessive muscular dystrophies caused by O-glycosylation defects in alpha-dystroglycans. It has three phenotypes based on severity: type A (severe forms of congenital muscular dystrophy [CMD] with brain and eye abnormalities, including Walker-Warburg syndrome [WWS], muscle-eye-brain disease [MEB], and Fukuyama CMD [FCMD]), type B (CMD with or without intellectual disability), and type C (a mild form of limb-girdle muscular dystrophy [LGMD]) ( Song et al, 2021 ).…”