Background: Congenital muscular dystrophy (CMD) refers to hypotonia and delayed motor development that is manifested at or near the birth. Additional presentations have been observed in CMD syndromes.
Methods: Thorough clinical examinations were performed on two unrelated Iranian families with typical symptoms of CMD and uncommon features such as intellectual disability and nephrolithiasis. The genomic DNA of probands were subjected to whole exome sequencing. Following the detection of candidate variants with a bioinformatic pipeline, the familial co-segregation analysis was carried out using polymerase chain reaction-based Sanger sequencing.
Results: We identified a missense homozygous variant in the fukutin-related protein (FKRP) gene (c.968G>A, p.Arg323His) related to CMD-dystroglycanopathy type B5 (MDDGB5) and a frameshift homozygous variant in the selenoprotein N (SELENON) gene (c.1446delC, p.Asn483Thrfs*11) associated with congenital rigid-spine muscular dystrophy 1 (RSMD1), which were completely segregated with the phenotypes in the families. These variants were not found in either the 1000 Genomes Project or the Exome Aggregation Consortium. The present study provides the first report of these homozygous sequence variants in Iran. Moreover, our study was the first observation of nephrolithiasis in FKRP-related dystroglycanopathy and intellectual disability in SELENON-related myopathies. Based on in silico studies and molecular docking, these variations induced pathogenic effects on the proteins.
Conclusions: Our findings extend the genetic database of Iranian patients with CMD and, in general, the phenotypical spectrum of syndromic CMD. It is recommended to consider these variants for a more accurate clinical interpretation, prenatal diagnosis and genetic counseling in families with a history of CMD, especially in those combined with cognitive impairments or renal dysfunctions.
Keywords: FKRP; SELENON; congenital muscular dystrophy; intellectual disability; whole exome sequencing.
© 2020 John Wiley & Sons, Ltd.