分子诊断技术的改进的分辨率使得能够检测更小尺寸的外显子水平拷贝数变体(CNV)。使用大型临床队列可以更好地识别CNV对常染色体隐性(AR)病症的贡献。
我们回顾性调查了接受染色体微阵列分析的病例中CNVs对AR状况的贡献(CMA,N=〜70,000)和/或临床外显子组测序(ES,贝勒遗传学的N=〜12,000);大多数患有儿科发作的神经发育障碍。
CNVs导致87例病例的双等位基因变异,包括81个单身和三个受影响的兄弟姐妹对。70例CNVs影响两个等位基因,和17具有反式的CNV和单核苷酸变体(SNV)/indel。总的来说,94.3%的AR-CNV影响一个基因;其中41.4%是单外显子,35.0%是多外显子部分基因事件。69%的纯合AR-CNV嵌入在纯合基因组间隔中。五例病例有大量缺失,揭开了完整等位基因上的SNV/indel的隐性病症,导致多种分子诊断。
AR-CNVs通常尺寸较小,世代相传,并且由于临床CNV检测方法的局限性而被低估。我们来自大型临床队列的发现强调了整合的CNV和SNV/indel分析,以进行精确的临床和分子诊断,尤其是在基因组疾病的背景下。
Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.
We retrospectively investigated the CNVs\' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.
CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.
AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.