Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly. Neuropsychiatric evaluation demonstrated a novel phenotype: an unusually large discrepancy between non-verbal capacities (borderline-impaired WISC-IV index scores of 70 for Working Memory and 68 for Processing Speed) vs. strong verbal skills – scores of 126 for Verbal Comprehension (superior) and 111 for Perceptual Reasoning (normal). HYDIN2 has been hypothesized to underlie macrocephaly and perhaps cognitive deficits in this syndrome, but assessment of HYDIN2 copy number by microarray is difficult because of extensive segmental duplications. We performed whole-genome sequencing which supported HYDIN2 duplication (chr1:146,370,001-148,590,000, 2.22 Mb, hg38). To evaluate copy number more rigorously we developed droplet digital PCR assays of HYDIN2 (targeting unique 1 kb and 6 kb insertions) and its paralog HYDIN (targeting a unique 154 bp segment outside the HYDIN2 overlap). In an independent cohort, ddPCR was concordant with previous microarray data. Duplication of HYDIN2 was confirmed in the patient by ddPCR. This case demonstrates that a large discrepancy of verbal and non-verbal abilities can occur in 1q21.1 duplication syndrome, but it remains unclear whether this has a specific genomic basis. These ddPCR assays may be useful for future research on HYDIN2 copy number.

在约0.03％的成年人中观察到染色体1q21.1的微复制。它具有高度可变的，不完全渗透的表型，其中可能包括智力障碍，全球发育迟缓，特定的学习障碍，自闭症，精神分裂症，心脏异常和畸形。我们通过CGH芯片评估了一名重复1q21.1的10岁男性。他表现出主要的注意力缺陷，语音障碍，精细运动技能差，畸形和轻度自闭症，但没有典型的大头畸形。神经精神病学评估显示出一种新的表型：非语言能力（工作记忆的边界受损的WISC-IV指数得分为70，处理速度为68）之间的异常差异非常大。HYDIN2被假设为该综合征的大头畸形症和认知功能障碍的基础，但是由于广泛的节段重复，通过微阵列评估HYDIN2拷贝数是困难的。我们进行了支持HYDIN2复制的全基因组测序（chr1：146,370,001-148,590,000，2.22 Mb，hg38）。为了更严格地评估拷贝数，我们开发了HYDIN2（靶向独特的1 kb和6 kb插入）及其旁系同源物HYDIN（靶向HYDIN2重叠区之外的独特154 bp片段）的液滴数字PCR分析。在一个独立的队列中，ddPCR与以前的微阵列数据一致。HYDIN2的重复通过ddPCR在患者身上得到证实。该案例表明，在1q21.1复制综合征中，言语和非言语能力可能存在很大差异，但尚不清楚这是否具有特定的基因组基础。这些ddPCR测定法可能对将来对HYDIN2拷贝数的研究有用。