Intellectual disability (ID) is a large group of neurodevelopmental disorders characterized by a congenital limitation in intellectual functioning (reasoning, learning, and problem solving), adaptive behavior (conceptual, social, and practical skills), originated at birth and manifested before the age of 18. By whole exome sequencing of five consanguineous Pakistani families presenting hallmark features of ID, global developmental delay, aggressive and self-injurious behaviors, microcephaly, febrile seizures and facial dysmorphic features, we identified three novel homozygous missense variants (NM_024298.5: c.588G > T; p.Trp196Cys, c.736 T > C; p.Tyr246His and c.524A > C; p. Asp175Ala) and one rare homozygous in-frame deletion variant (c.758_778del;p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) gene previously associated with autosomal recessive neurodevelopmental disorder. The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic MBOAT7 variants in five cases of autosomal recessive ID further highlight the importance of this genes in proper brain function and development.

中文翻译：

---

外显子组测序鉴定出 MBOAT7 中与神经发育障碍相关的纯合变异

智力障碍 (ID) 是一大类神经发育障碍，其特征是智力功能（推理、学习和解决问题）、适应性行为（概念、社交和实践技能）先天性受限，起源于出生并在年龄之前表现出来18. 通过对五个具有智力障碍、整体发育迟缓、攻击性和自残行为、小头畸形、热性惊厥和面部畸形特征的巴基斯坦近亲家庭进行全外显子测序，我们鉴定出了三种新的纯合错义变异（NM_024298.5： c.588G > T；p.Trp196Cys，c.736 T > C；p.Tyr246His 和 c.524A > C；p. Asp175Ala) 和一种罕见的纯合框内缺失变体 (c.758_778del；p.Glu253_Ala259del)膜结合 O-酰基转移酶家族成员 7 ( MBOAT7)基因先前与常染色体隐性神经发育障碍相关。通过所有家庭成员的桑格测序验证了变异的分离。野生型和突变蛋白的计算机同源性模型揭示了两种蛋白结构的实质性变化，表明可能对功能产生影响。在五例常染色体隐性遗传 ID 病例中鉴定和验证了新的致病性MBOAT7变异，进一步凸显了该基因在正常大脑功能和发育中的重要性。