Philips A K, Pinelli M, de Bie C I, Mustonen A, Määttä T, Arts H H, Wu K, Roepman R, Moilanen J S, Raza S, Varilo T, Scala G, Cocozza S, Gilissen C, van Gassen K L I, Järvelä I
Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Centre, Nijmegen, the Netherlands.
Clin Genet. 2017 Jan;91(1):100-105. doi: 10.1111/cge.12821. Epub 2016 Jul 12.
Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.
智力残疾（ID）是我们社会中的一个主要健康问题。由于其高度异质性，ID的遗传病因仍然未知。在此，我们报告了两个芬兰家庭和一个荷兰家庭，这些家庭中的受影响个体表现出轻度至中度ID、神经精神症状和语言发育迟缓。通过利用全外显子组测序（WES），我们在来自两个芬兰近亲家庭的7名受影响个体中鉴定出一个奠基者错义变体c.983T>C（p.Leu328Pro），在来自一个荷兰近亲家庭的1名受影响个体中鉴定出12号染色体上C12orf4基因的一个缺失c.799_1034-429delinsTTATGA（p.Gln267fs）。这两个变体在各自家庭中均作为常染色体隐性性状共分离。对p.Leu328Pro变体的筛查显示，在芬兰东北部亚隔离人群的匿名当地献血者中该变体富集，携带频率为1:53，这与该地区其他具有奠基者效应的疾病突变相似。迄今为止，仅报道了一个阿拉伯家庭，该家庭中有3名受影响个体在C12orf4基因中存在移码插入变体。总之，我们扩展并确定了C12orf4变体的临床和突变谱。我们的研究结果表明C12orf4是常染色体隐性ID的致病基因。
