Zhang Stephanie Q, Fleischer Julie, Al-Kateb Hussam, Mito Yoshiko, Amarillo Ina, Shinawi Marwan
Saint Louis University School of Medicine, St. Louis, MO, USA.
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; Southern Illinois University, Springfield, IL, USA.
Eur J Med Genet. 2020 Mar;63(3):103736. doi: 10.1016/j.ejmg.2019.103736. Epub 2019 Aug 15.
Deletions and duplications involving the CNTN4 gene, which encodes for the contactin 4 protein, have been reported in children with autism spectrum disorder (ASD) and other neurodevelopmental phenotypes. In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this gene were mostly inherited from unaffected fathers, raising questions regarding reduced penetrance and potential parent-of-origin effect. Our findings are compared with previously reported patients and patients in the DECIPHER database. The speech impairment in the three probands suggests a role for CNTN4 in language development. We discuss potential factors contributing to phenotypic heterogeneity and reduced penetrance and attempt to find possible genotype-phenotype correlation. Larger cohorts are needed for comprehensive and unbiased phenotyping and molecular characterization that may lead to better understanding of the underlying mechanisms of reduced penetrance, variable expressivity, and potential parent-of-origin effect of copy number variants encompassing CNTN4.
据报道，患有自闭症谱系障碍（ASD）和其他神经发育表型的儿童存在涉及接触蛋白4（CNTN4）基因的缺失和重复，该基因编码接触蛋白4。在本研究中，我们对来自三个无关家庭的个体进行了临床和基因特征分析，这些个体在CNTN4基因内存在拷贝数变异（CNV）（1例缺失和2例重复）。患者表现出认知延迟（3/3）、生长受限（3/3）、运动延迟（2/3）以及热性惊厥/癫痫（2/3）。与先前报道不同的是，所有先证者均表现出言语失用或言语延迟，且未诊断为ASD。对缺失型先证者和2例重复型先证者中的1例进行的亲代研究显示，CNTN4的CNV源自父亲。有趣的是，先前记录的涉及该基因的CNV大多从未受影响的父亲遗传而来，这引发了关于外显率降低和潜在亲源效应的问题。我们将研究结果与先前报道的患者以及DECIPHER数据库中的患者进行了比较。三位先证者的言语障碍表明CNTN4在语言发育中起作用。我们讨论了导致表型异质性和外显率降低的潜在因素，并试图寻找可能存在的基因型-表型相关性。需要更大的队列进行全面且无偏倚的表型分析和分子特征分析，这可能有助于更好地理解涉及CNTN4的拷贝数变异的外显率降低、可变表达以及潜在亲源效应的潜在机制。
