Severe SPTBN4-Related Neurodevelopmental Disorder: Case Report of Two Siblings with Lethal Outcomes.

Spectrin beta non-erythrocytic 4 (SPTBN4) disorder is a rare yet impactful condition that is also known as neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND). It is caused by homozygous or compound heterozygous mutations in the SPTBN4 gene, which encodes beta IV (βIV) spectrin primarily found in neurons and pancreatic islets. Here, we report two male siblings from a Syrian non-consanguineous (possibly distantly related) family diagnosed with SPTBN4 disorder. Both patients exhibited severe failure to thrive, hypotonia, dysphagia, and global developmental delay, initially suggesting spinal muscular atrophy (SMA). Further testing has ruled out SMA for both patients, and the older sibling died undiagnosed at the age of 1 year and 6 months. Subsequently, whole genome sequencing (WGS) revealed a novel homozygous nonsense c.508 A > T p. (Lys170*) variant in the SPTBN4 gene in the younger sibling, and he died at the age of 2 years and 7 months with a presumed diagnosis of NEDHND. Upon the confirmation of the mutation in DNA stored from the older sibling, the variant was reclassified from a variant of uncertain significance (VUS) to likely pathogenic, enabling prenatal genetics testing for future pregnancies. This case study reports a novel lethal genetic variant in the SPTBN4 gene in two siblings, capturing their clinical progression, and comparing them with recent cases to highlight both common and unique features associated with NEDHND. The report’s findings provide valuable insights into the UAE cohort, contributing to the limited body of knowledge on variants present in Arab populations.