Yu T, Li J, Li N, Liu R, Ding Y, Chang G, Chen Y, Shen Y, Wang X, Wang J
Department of Medical Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Int J Obes (Lond). 2016 Dec;40(12):1935-1941. doi: 10.1038/ijo.2016.160. Epub 2016 Sep 22.
Uniparental disomy (UPD) is an unusual situation wherein two homologous chromosomes are inherited from the same parent. UPDs can cause clinical abnormalities owing to the aberrant dosage of genes regulated by epigenetic imprinting or homozygosity of variants for recessive phenotypes. The aim of this study was to identify the genetic cause of the obesity and developmental delay phenotype in a 3-year-old Chinese boy.
Chromosomal microarray analysis (CMA) was used for detecting potential copy number variations (CNVs) and homozygous segments. Whole-exome sequencing (WES) identified sequence variants. Sanger sequencing further confirmed the variants in GPBAR1 and CAPN10 both in the patient and the parents.
No clinically significant CNVs were identified by CMA but a complete UPD of chromosome 2 (UPD2) was revealed in the patient. WES identified a total of 13 rare homozygous single-nucleotide variants (SNVs) on chromosome 2. Among the 13 SNVs, a nonsense variation in GPBAR1 (c.753T>G; p.Y251*) and a missense variation in CAPN10 (c.413C>T; p.S138F) were evaluated as candidate disease-causing variants based on their functional impacts to their respective protein and the biological relevance of the genes to the clinical presentation of our patient. Both GPBAR1 and CAPN10 variants were detected in the patient's mother in a heterozygous state, indicating that the patient had maternal UPD2. No other clinically relevant variants were identified.
Homozygosity of rare recessive variations caused by UPD2 likely contributed to the phenotypes of our patient. Based on emerging evidence, the nonsense variation in GPBAR1 and the missense variation in CAPN10 are considered as causally related to our patient's phenotype, that is, obesity and delayed development, respectively. The present study further supports the role of GPBAR1 in obesity and the role of calpain-10 in neurological function.
单亲二体（UPD）是一种异常情况，即两条同源染色体均来自同一亲本。由于表观遗传印记调控的基因剂量异常或隐性表型变异的纯合性，UPD可导致临床异常。本研究旨在确定一名3岁中国男孩肥胖和发育迟缓表型的遗传原因。
采用染色体微阵列分析（CMA）检测潜在的拷贝数变异（CNV）和纯合片段。全外显子组测序（WES）鉴定序列变异。桑格测序进一步证实了患者及其父母中GPBAR1和CAPN10基因的变异。
CMA未发现具有临床意义的CNV，但在患者中发现了2号染色体的完全单亲二体（UPD2）。WES在2号染色体上共鉴定出13个罕见的纯合单核苷酸变异（SNV）。在这13个SNV中，基于GPBAR1基因的无义变异（c.753T>G；p.Y251*）和CAPN10基因的错义变异（c.413C>T；p.S138F）对各自蛋白质的功能影响以及基因与患者临床表现之间的生物学相关性，将它们评估为候选致病变异。患者母亲中检测到GPBAR1和CAPN10变异均为杂合状态，表明患者存在母源性UPD2。未发现其他具有临床相关性的变异。
UPD2导致的罕见隐性变异纯合性可能是患者表型的原因。基于新出现的证据，GPBAR1基因的无义变异和CAPN10基因的错义变异分别被认为与患者的肥胖和发育迟缓表型存在因果关系。本研究进一步支持了GPBAR1在肥胖中的作用以及钙蛋白酶-10在神经功能中的作用。
