Abstract
BackgroundNeurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden.MethodsWe investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals.ResultsWe identified a homozygous splice site variant (NM_000521:c.445 + 1G > T) in the hexosaminidase B (HEXB) gene confirming a diagnosis of Sandhoff disease (SD; type II GM2-gangliosidosis), an autosomal recessive lysosomal storage disorder caused by deficiency of hexosaminidases in a single family. In two further unrelated families, we identified a homozygous frameshift variant (NM_024298.3:c.758_778del; p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) as the likely cause of disease. MBOAT7 gene variants have recently been identified as a cause of intellectual disability (ID), seizures and autistic features.ConclusionsWe identified two metabolic disorders of lipid biosynthesis within three Pakistani families presenting with undiagnosed neurodevelopmental conditions. These findings enabled an accurate neurological disease diagnosis to be provided for these families, facilitating disease management and genetic counselling within this population. This study consolidates variation within MBOAT7 as a cause of neurodevelopmental disorder, broadens knowledge of the clinical outcomes associated with MBOAT7-related disorder, and confirms the likely presence of a regionally prevalent founder variant (c.758_778del; p.Glu253_Ala259del) in Pakistan.
Highlights
Neurological disorders are a common cause of morbidity and mortality within Pakistani populations
We investigate three consanguineous Pakistani families with features of autosomal recessive neurological disorders in order to identify a precise molecular diagnosis using a combination of genome wide Single Nucleotide Polymorphism (SNP) mapping and whole exome sequencing (WES)
Onset of generalised tonic-clonic (GTC) seizures with excessive startle reflex were observed at 7 months of age with increasing frequency and severity over time, control was improved after the introduction of phenobarbital
Summary
Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden. Neurological disorders are an increasing burden in developing countries due to improving life expectancy, urbanisation of the population and improved health care and diagnosis. Pakistani populations compared with more economically developed countries [1, 2]. Sandhoff disease (SD)(MIM 268800) is an autosomal recessive lysosomal lipid storage disorder caused by biallelic variants within the HEXB gene, resulting in deficiency of HEXA and HEXB enzymes [4] and intralysosomal accumulation of GM2
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