Genetic blueprint of congenital muscular dystrophies with brain malformations in Egypt: A report of 11 families

Abstract

Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders.

Keywords: Congenital muscular dystrophy; Dystroglycanopathy; FLVCR1; Hydrocephalus; Lissencephaly.

Fig. 1

Pedigrees for cases with family history of CMD. A S1 was born from a 1^st cousin union and had a distant cousin diagnosed with hydrocephalus. B S3 was born from a 1^st cousin union and had a deceased younger brother with hydrocephalus and failure to thrive. C S5 was born from a 1^st cousin union and had two siblings with severe hypotonia who died in infancy. D S11 and S12 are siblings and had an older sib with CMD who died at age 9

Fig. 2

Brain imaging for selected cases. A Axial T2 MRI image showing the classical T2 hyperintense signal within the periventricular white matter in case S9. B, C Axial T2 MRI images of case S8 showing abnormal hyperintense signal within the periventricular white matter with additional cortical malformations including bilateral occipital segmental lissencephaly (arrows in C). D, E: Axial (D) and sagittal (E) T2 MRI images of case S1 showing diffuse cobblestone type II lissencephaly with flattening of the entire cerebral mantle as well as hypoplastic cerebellum and pons and Z-shaped brainstem (arrow in E). F, G: Different axial T2 MRI images of case S2 showing supratentorial abnormal perisylvian cortical development (arrows in F), cerebellar hypoplasia, small size pons, and abnormal right eye globe with abnormal right lens configuration and intra vitreous hemorrhage (asterisk in G). H, I: Coronal (H) and sagittal (I) non contrast CT images of case S5 showing the supratentorial brain nearly replaced by CSF apart from the interhemispheric fissure, also associated with hypoplastic cerebellum and kinked brain stem structures. J, K: Axial T2 MRI images of case S7 showing periventricular white matter abnormalities in addition to hypoplasia of both cerebellar hemispheres with multiple bilateral microcysts as well as dysplastic features