Heterozygous structural variation mimicking homozygous missense mutations in NEU1 associated with presenting clinical signs in eyes alone

Biallelic mutations in neuraminidase 1 (<i>NEU1</i>) are associated with cherry-red spots. Whole genome sequencing contributes to eliminating pseudo-homozygous mutations when large-scale deletion of one allele in <i>NEU1</i> and other genes occurs. Bilateral cherry-red spots in the macula were the only detectable sign in an 11-year-old girl with reduced visual acuity over the last two years. Targeted exome sequencing of genes for inherited eye diseases identified a homozygous c.544A&gt;G (p.Ser182Gly) variation in the <i>NEU1</i> gene. This variant was also present in her mother in the heterozygous state but not in her father. Whole genome sequencing identified a heterozygous 27.5 kb deletion involving the whole coding exons of <i>NEU1</i> in her father. Sanger sequencing disclosed the breakpoint of the deletion. This heterozygous deletion was also detected in the patient, so the c.544A&gt;G mutation should be heterozygous in the patient. The results of this case remind us of the limitations of routine exome sequencing and the need to perform segregation studies and deletion/duplication analysis or WGS if parental studies do not support exome findings. In addition, patients with sialidosis may present with ocular manifestations without systemic signs early in the disease course.

神经氨酸酶1（neuraminidase 1，NEU1）的双等位基因突变与樱桃红斑相关。当NEU1及其他基因发生单个等位基因大规模缺失时，全基因组测序（whole genome sequencing，WGS）有助于排除假纯合突变。一名11岁女孩在过去两年间出现视力下降，其眼底黄斑区双侧樱桃红斑是唯一可检测到的体征。针对遗传性眼病相关基因的靶向外显子组测序（targeted exome sequencing）显示，该患者的NEU1基因存在纯合的c.544A>G（p.Ser182Gly）变异。该变异在其母亲体内以杂合状态存在，但未在父亲体内检出。全基因组测序在其父亲体内检测到一段覆盖NEU1全部编码外显子的27.5kb杂合缺失，桑格测序（Sanger sequencing）明确了该缺失的断点。该患者体内同样检测到该杂合缺失，因此患者体内的c.544A>G突变实际应为杂合状态。本病例的结果提醒我们，常规外显子组测序（routine exome sequencing）存在局限性，若亲本检测结果与外显子组测序结果不符，则需开展分离分析、缺失/重复分析或全基因组测序。此外，唾液酸苷酶缺乏症（sialidosis）患者在病程早期可能仅表现出眼部症状，而无全身体征。