BACKGROUND 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. METHODS We 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. RESULTS We 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. CONCLUSIONS We 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.

中文翻译：

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HEXB和MBOAT7基因的纯合变异是近亲家庭神经系统疾病的基础。

背景技术神经系统疾病是巴基斯坦人群中发病和死亡的常见原因。这是医疗保健中最重要的挑战之一，终身社会经济负担沉重。方法我们使用全基因组SNP作图和整个外显子组测序（WES），调查了无法解释的常染色体隐性遗传神经疾病的三个巴基斯坦家庭的病因。结果我们在己糖胺酶B（HEXB）基因中鉴定出纯合的剪接位点变体（NM_000521：c.445 + 1G> T），证实了桑德霍夫病（SD； II型GM2-神经节苷脂病）的诊断，这是一种常染色体隐性溶酶体贮积病引起的缺乏一个家族中的己糖胺酶。在另外两个不相关的家庭中，我们在膜结合的O-酰基转移酶家族成员7（MBOAT7）中鉴定了一个纯合的移码变异（NM_024298.3：c.758_778del; p.Glu253_Ala259del）。最近已确定MBOAT7基因变异是导致智障（ID），癫痫发作和自闭症特征的原因。结论我们在三个巴基斯坦家庭中鉴定出了两个脂类生物合成代谢紊乱，表现出未确诊的神经发育状况。这些发现使得能够为这些家庭提供准确的神经系统疾病诊断，从而促进该人群的疾病管理和遗传咨询。这项研究巩固了MBOAT7中引起神经发育障碍的变异，拓宽了与MBOAT7相关疾病相关的临床结局的知识，