Abstract:
The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents.
摘要:
全外显子组测序(WES)的广泛应用导致了多位点致病变异(MPV)的发现,定义为患者发生的两种或两种以上不同或重叠的孟德尔疾病,导致混合表型。在这项研究中,我们报道了一名常染色体隐性遗传原发性小头畸形-5(MCPH5)和肾病性膀胱炎的儿童。先证者是近亲父母的第一个孩子,呈现复杂的表型,包括神经发育迟缓,小头畸形,生长限制,骨成熟显著延迟,间脑,和神经元迁移的异常,畏光,和肾小管酸中毒.WES揭示了两种致病性和纯合变体:ASPM基因中的c.4174C>T变体和CTNS基因中的c.382C>T变体,解释复杂的表型。文献综述表明,大多数在隐性疾病基因中具有两个变异的患者都是近亲父母所生的。据我们所知,例如,本文描述的患者是在ASPM和CTNS基因两者中都具有致病性变体的第一患者。这些发现强调了在通过全基因组测试方法调查的复杂表型患者中搜索MPV的重要性。尤其是那些亲生父母的病人。