Kamath Arveen, Linden Stefanie C, Evans Ffion M, Hall Jeremy, Jose Sian F, Spillane Sally A, Hardie Alan D R, Morgan Sian M, Pilz Daniela T
Institute of Medical Genetics, All Wales Medical Genetics Service, University Hospital of Wales, Cardiff, United Kingdom.
Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom.
Am J Med Genet B Neuropsychiatr Genet. 2018 Jul;177(5):520-528. doi: 10.1002/ajmg.b.32643.
Copy number variants at chromosome 17q12 have been associated with a spectrum of phenotypes. Deletions of 17q12 are well described and associated with maturity onset diabetes of the young type 5 (MODY5) and cystic renal disease (HNF1β) as well as cognitive impairment and seizures. Duplication of 17q12 is emerging as a new genetic syndrome, associated with learning disability, seizures, and behavioral problems. The duplication is often inherited from an apparently unaffected parent. Here, we describe a three-generation family with multiple individuals carrying a17q12 microduplication with varying clinical features, consistent with variable penetrance. The proband who inherited a 1.8 Mb interstitial 17q12 duplication from his mother presented with developmental delay, behavioral problems, and mild dysmorphism. One of his sisters, his maternal uncle, and his maternal grandmother also carry the 17q12 microduplication. Clinical features of the carriers include renal problems, diabetes mellitus, learning difficulties, epilepsy and mental illness. Cognitive abilities range from normal function to moderate impairment (full-scale IQ range: 52-99). In light of recent reports of association of this locus with schizophrenia, we performed a detailed psychiatric assessment and confirmed that one family member has symptoms consistent with a diagnosis of schizophrenia and another has a prodromal syndrome with attenuated positive symptoms of psychosis. This report extends the clinical phenotype associated with the 17q12 microduplication and highlights the phenotypic variability.
17号染色体17q12区域的拷贝数变异与一系列表型相关。17q12区域的缺失已有充分描述，与青少年发病的成年型糖尿病5型（MODY5）、囊性肾病（HNF1β）以及认知障碍和癫痫发作有关。17q12区域的重复正成为一种新的遗传综合征，与学习障碍、癫痫发作和行为问题相关。这种重复通常从表面上未受影响的父母一方遗传而来。在此，我们描述了一个三代家族，其中多个个体携带17q12微重复，具有不同的临床特征，符合可变外显率。先证者从其母亲那里遗传了一个1.8 Mb的17q12间质性重复，表现出发育迟缓、行为问题和轻度畸形。他的一个姐妹、他的舅舅和他的外祖母也携带17q12微重复。携带者的临床特征包括肾脏问题、糖尿病、学习困难、癫痫和精神疾病。认知能力范围从正常功能到中度损害（全量表智商范围：52 - 99）。鉴于最近有关于该基因座与精神分裂症关联的报道，我们进行了详细的精神科评估，证实一名家族成员有符合精神分裂症诊断的症状，另一名有精神病性症状减轻的前驱综合征。本报告扩展了与17q12微重复相关的临床表型，并突出了表型变异性。
