Nemirovsky Sergio I, Córdoba Marta, Zaiat Jonathan J, Completa Sabrina P, Vega Patricia A, González-Morón Dolores, Medina Nancy M, Fabbro Mónica, Romero Soledad, Brun Bianca, Revale Santiago, Ogara María Florencia, Pecci Adali, Marti Marcelo, Vazquez Martin, Turjanski Adrián, Kauffman Marcelo A
Plataforma de Bioinformática Argentina, Instituto de Cálculo, Pabellón 2, Ciudad Universitaria, Facultad de Ciencias Exactas y Naturales, UBA, Buenos Aires, Argentina.
Consultorio y Laboratorio de Neurogenética. Hospital JM Ramos Mejía. IBCN Eduardo de Robertis UBA-CONICET, Buenos Aires, Argentina.
PLoS One. 2015 Feb 3;10(2):e0116358. doi: 10.1371/journal.pone.0116358. eCollection 2015.
Clinical genomics promise to be especially suitable for the study of etiologically heterogeneous conditions such as Autism Spectrum Disorder (ASD). Here we present three siblings with ASD where we evaluated the usefulness of Whole Genome Sequencing (WGS) for the diagnostic approach to ASD.
We identified a family segregating ASD in three siblings with an unidentified cause. We performed WGS in the three probands and used a state-of-the-art comprehensive bioinformatic analysis pipeline and prioritized the identified variants located in genes likely to be related to ASD. We validated the finding by Sanger sequencing in the probands and their parents.
Three male siblings presented a syndrome characterized by severe intellectual disability, absence of language, autism spectrum symptoms and epilepsy with negative family history for mental retardation, language disorders, ASD or other psychiatric disorders. We found germline mosaicism for a heterozygous deletion of a cytosine in the exon 21 of the SHANK3 gene, resulting in a missense sequence of 5 codons followed by a premature stop codon (NM_033517:c.3259_3259delC, p.Ser1088Profs*6).
We reported an infrequent form of familial ASD where WGS proved useful in the clinic. We identified a mutation in SHANK3 that underscores its relevance in Autism Spectrum Disorder.
临床基因组学有望特别适用于研究病因异质性疾病，如自闭症谱系障碍（ASD）。在此，我们报告了三名患有ASD的兄弟姐妹，评估了全基因组测序（WGS）在ASD诊断方法中的实用性。
我们鉴定出一个在三名兄弟姐妹中患有未明确病因的ASD的家族。我们对三名先证者进行了WGS，并使用了先进的综合生物信息学分析流程，对位于可能与ASD相关的基因中的已鉴定变异进行了优先级排序。我们通过先证者及其父母的桑格测序验证了这一发现。
三名男性兄弟姐妹表现出一种综合征，其特征为严重智力残疾、无语言能力、自闭症谱系症状和癫痫，家族中无智力迟钝、语言障碍、ASD或其他精神疾病的病史。我们发现SHANK3基因外显子21中一个胞嘧啶杂合缺失的生殖系嵌合体，导致5个密码子的错义序列，随后是一个提前终止密码子（NM_033517:c.3259_3259delC，p.Ser1088Profs*6）。
我们报告了一种罕见的家族性ASD形式，其中WGS在临床中被证明是有用的。我们在SHANK3中鉴定出一个突变，突出了其在自闭症谱系障碍中的相关性。
