Compound heterozygous loss of function variants in MYL9 in a child with megacystis–microcolon–intestinal hypoperistalsis syndrome,Molecular Genetics & Genomic Medicine

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Compound heterozygous loss of function variants in MYL9 in a child with megacystis–microcolon–intestinal hypoperistalsis syndrome
Molecular Genetics & Genomic Medicine ( IF 1.5 ) Pub Date : 2020-10-08 , DOI: 10.1002/mgg3.1516
Justin L Kandler ₁ , Evgenia Sklirou ₂ , Audrey Woerner ₂ , Leslie Walsh ₂ , Eleina Cox ₁ , Yuan Xue ₁

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Megacystis–microcolon–intestinal hypoperistalsis syndrome (MMIHS), or “visceral myopathy,” is a severe early onset disorder characterized by impaired muscle contractility in the bladder and intestines. Five genes are linked to MMIHS: primarily ACTG2, but also LMOD1, MYH11, MYLK, and MYL9. Here we describe a three‐year‐old girl with bilateral hydronephrosis diagnosed at 20 weeks gestation and congenital mydriasis (both of which have been previously observed among individuals with MMIHS). A clinical diagnosis of MMIHS was made based upon the presence of megacystis, lack of urinary bladder peristalsis, and intestinal pseudo‐obstruction. After initial testing of ACTG2 was negative, further sequencing and deletion/duplication testing was performed on the LMOD1, MYH11,MYLK, and MYL9 genes. We identified two heterozygous loss of function variants in MYL9: an exon 4 deletion and a nine base pair deletion that removes the canonical splicing donor site at exon 2 (NM_006097.5:c.184+2_184+10del). Parental testing confirmed these variants to be in trans in our proband. To our knowledge, only one other individual with MMIHS has biallelic mutations in MYL9 (a homozygous deletion encompassing exon 4). We suggest MYL9 be targeted on genetic testing panels for MMIHS, smooth muscle myopathies, and cardiovascular phenotypes.

中文翻译：

巨膀胱-小结肠-肠蠕动减退综合征患儿的 MYL9 复合杂合性功能缺失变异

巨膀胱-小结肠-肠蠕动减退综合征 (MMIHS) 或“内脏肌病”是一种严重的早发性疾病，其特征是膀胱和肠道的肌肉收缩力受损。五个基因与 MMIHS 相关：主要是ACTG2，还有LMOD1、MYH11、MYLK和MYL9。在这里，我们描述了一名三岁女孩，她在妊娠 20 周时被诊断患有双侧肾积水和先天性瞳孔散大（之前在 MMIHS 患者中观察到这两种情况）。MMIHS 的临床诊断是基于巨膀胱的存在、膀胱缺乏蠕动和肠假性梗阻。ACTG2初步测试后为阴性，对LMOD1、MYH11、MYLK和MYL9基因进行了进一步的测序和缺失/重复测试。我们在MYL9中发现了两个杂合的功能缺失变体：一个外显子 4 缺失和一个九碱基对缺失，该缺失去除了外显子 2 处的典型剪接供体位点 (NM_006097.5:c.184+2_184+10del)。父母测试证实这些变异在我们的先证者中是反式的。据我们所知，只有一名 MMIHS 患者在 MYL9 中有双等位基因突变（包含外显子 4 的纯合缺失）。我们建议MYL9针对 MMIHS、平滑肌肌病和心血管表型的基因检测面板。

更新日期：2020-11-16

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