A homozygous nonsense variant in DYM underlies Dyggve–Melchior–Clausen syndrome associated with ectodermal features

• Published in: Molecular biology reports 2020-09, Vol.47 (9), p.7083-7088
• Main Authors: Abdullah, Shah, Pashmina Wiqar, Nawaz, Shoaib, Hussain, Shabir, Ullah, Asmat, Basit, Sulman, Ahmad, Wasim
• Format: Article
• Language: English
• Subjects: Adult; Animal Anatomy; Animal Biochemistry; Biomedical and Life Sciences; Bone dysplasia; Chromosome 18; Chromosomes; Codon, Nonsense; Dwarfism; Dwarfism - genetics; Dwarfism - pathology; Dysplasia; Female; Follicles; Genome, Human; Genome-Wide Association Study; Genomes; Hair; Histology; Homozygote; Humans; Iliac crest; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Intracellular Signaling Peptides and Proteins - genetics; Life Sciences; Male; Molecular biology; Morphology; Mutation; Original Article; Osteochondrodysplasias - congenital; Osteochondrodysplasias - genetics; Osteochondrodysplasias - pathology; Polymorphism, Single Nucleotide; Population studies; Scoliosis; Single-nucleotide polymorphism; Skeleton; Transcription; X-rays
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-020-05774-z

Dyggve melchior clausen syndrome (DMC, MIM 223800) is a very rare autosomal recessive form of skeletal dysplasia associated with various degrees of mental retardation. It is characterized by a progressive spondyloepimetaphyseal dysplasia (SEMD) with disproportionate short stature, generalized platyspondyly and lacy iliac crest. Here, we report characterization of large consanguineous family segregating DMC in autosomal recessive manner. Scanning SNP-based human genome identified a 5.3 Mb homozygous region on chromosome 18q21.1-q21.2. Sanger sequencing of the DYM gene, located in the homozygous region, revealed a novel homozygous nonsense variant [c.59 T > A; p.(Leu20*)] in affected members of the family. Analysis of the mRNA, extracted from hair follicles of an affected individual, suggested non-sense mediated decay (NMD) of the truncated transcript. This is the first nonsense and fourth loss of function variant in the DYM gene, causing DMC, reported in the Pakistani population. This study not only extended spectrum of the mutations in the DYM gene but will also facilitate diagnosis of similar other cases in Pakistani population.