Department of Speech and Hearing Science, Arizona State University, 975 S. Myrtle Ave, Tempe, AZ, 85287-0102, USA.
Department of Communication Sciences and Disorders, Saint Louis University, Saint Louis, MO, USA.
Behav Genet. 2019 Jul;49(4):399-414. doi: 10.1007/s10519-019-09957-8. Epub 2019 Apr 4.
Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.
最近对自闭症谱系障碍（ASD）和儿童言语失用症（CAS）的研究基于表型得出了这些疾病共病的相互矛盾的结论。在一个有两个双受影响和一个未受影响后代的核心家庭中，评估了全外显子序列的单核苷酸和插入缺失变体和 CNV。受影响的兄弟姐妹而不是未受影响的兄弟姐妹在 WWOX 中共享一个罕见的有害复合杂合突变，该突变与 ASD 和运动控制都有关。此外，其中一个受影响的孩子携带 ASD 候选基因 RIMS1 的罕见有害新生突变。这两个受影响的孩子而不是他们未受影响的兄弟姐妹遗传了与 ASD 和/或 CAS 相关的有害变异。WWOX、RIMS1 和携带遗传变异的几个基因在产前和新生儿早期发育过程中在大脑中表达。结果表明，复合杂合性是 ASD 和 CAS 的原因，具有多效性基因效应，并且可能存在其他复杂的遗传效应。
