Phenotypic and molecular characterization of INPP5K-related congenital muscular dystrophy in four Egyptian patients

Abstract INPP5K -related congenital muscular dystrophy is an ultra-rare autosomal recessive disorder characterized by variable combinations of early-onset cataracts, proximal muscle weakness, elevated serum creatine kinase, and intellectual disability. To date, about 31 affected individuals have been reported worldwide, and the clinical and molecular spectrum of the disorder remains incompletely defined. Herein, we describe four patients from three unrelated consanguineous Egyptian families. All patients presented with hypotonia, proximal muscle weakness, microcephaly, waddling gait, elevated serum creatine kinase, and mild intellectual disability. Cataracts were identified in only two patients, highlighting the incomplete penetrance of this hallmark feature. Brain MRI was normal in two patients whereas mild asymmetry of the lateral ventricles and thin corpus callosum were identified in the remaining two patients. Axonal neuropathy and delayed puberty, features infrequently reported in INPP5K -related disease, were also observed in our cohort. Exome sequencing identified three homozygous INPP5K variants, including the recurrent p.(Ile50Thr) and two previously unreported missense variants: p.(Arg234Pro) within the catalytic 5-phosphatase domain and p.(Tyr349Ser) within the C-terminal SKICH domain. Both variants affected highly conserved residues, were absent from public population databases, and consistently predicted to be deleterious by multiple in-silico tools and protein structural modeling analyses. Our findings refine both the clinical and molecular spectrum of INPP5K -related muscular dystrophy and present the first report from Egypt and North Africa. In addition, the identification of variants affecting both major functional domains of the protein further supports the marked molecular and phenotypic heterogeneity associated with INPP5K deficiency.