Department of Translational Medicine-Medical Genetics and Genomic Medicine, School of Medical Sciences, State University of Campinas, Campinas 13083-887, São Paulo, Brazil.
Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Genes (Basel). 2022 Dec 16;13(12):2377. doi: 10.3390/genes13122377.
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 gene and a c.382C>T variant in the 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 and 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.
全外显子测序（WES）的广泛应用导致了多基因位致病性变异（MPV）的发现，MPV 定义为两个或更多不同或重叠的孟德尔疾病同时发生在一个患者身上，导致混合表型。在这项研究中，我们报告了一例常染色体隐性原发性小头畸形-5（MCPH5）伴胱氨酸贮积症的患儿。先证者是近亲父母的第一个孩子，表现出复杂的表型，包括神经发育迟缓、小头畸形、生长受限、骨成熟明显延迟、无脑回、神经元迁移异常、畏光和肾小管性酸中毒。WES 揭示了两个致病性的纯合变异： 基因中的 c.4174C>T 变异和 基因中的 c.382C>T 变异，解释了复杂的表型。文献复习表明，大多数携带隐性疾病基因中两个变异的患者是近亲父母所生。据我们所知，本文描述的患者是首例同时携带 基因和 基因致病性变异的患者。这些发现强调了在使用全基因组检测方法对复杂表型患者进行研究时，寻找 MPV 的重要性，尤其是对那些由近亲父母所生的患者。
