BACKGROUND

Pathogenic variants in SPTBN4 have been linked to autosomal recessive "neurodevelopmental disorder with hypotonia, neuropathy, and deafness" (MIM# 617519) known as NEDHND. The disorder is highlighted with neuropathy, muscle weakness, and infrequent appearance of seizures in the affected individuals. This study aims to investigate the natural history of the disease, present genetic and clinical appearance of the syndrome in a highly consanguineous population, Saudi Arabia, and finally provide an overview of the reported cases, their clinical features, and disease-causing variants.

METHODS

The study started with a search through neurology clinics and local databases and utilized genetic testing records after diagnosing a patient with NEDHND at our hospital (King Faisal Specialist Hospital and Research Centre, KFSHRC). Based on the search we have identified additional patients (in total, n = 10) with the disease and performed genetic testing using whole exome sequencing and confirmatory Sanger sequencing. We performed RT-PCR on RNA extracted from lymphoblastoid cell line from a patient who found to have an aberrant splicing variant. Finally, we comprehensively reviewed current literature and available data related to the disease.

RESULTS

We present natural history of SPTBN4-associated neurodevelopmental disorder with hypotonia, neuropathy, and deafness in addition to four Saudi families with ten affected individuals who share clinical features of NEDHND. We report three known mutations and one novel nonsense variant, highlight atypical clinical features related to cerebellar involvement, confirm the pathogenicity of a splicing variant by RT-PCR, and review the findings of previously reported patients.

CONCLUSION

Our study defines the clinical phenotype of a cohort of NEDHND in detail including the evolution of patients' clinical features, compares them to previously reported cases, and utilizes the existing data on the disease to direct development of a better prevention plan by means of genetic and preimplantation counseling. Our study may help and enable future clinical trials focusing on NEDHND in our country.