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Abstract

Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental disorder characterized by deficits in social communication and interaction, repetitive and restrictive behavior, extensive clinical and etiologic heterogeneity. ASD underlying genetic basis, range from effects of single genes to that of multiple genes and chromosomal regions, hallmarking the multifactorial and complex etiology. While a genetic etiology is identifiable in about one quarter of the cases, in the remaining three quarters it remains elusive. A family with two males affected by ASD was studied to identify the genetic basis of ASD in the family. Two siblings, a brother and his sister, each had a male child with ASD through marriage to their respective unrelated spouses. The first family [F1] has one affected male child; the second [F2] has one affected male and one unaffected female children. The father of F1 and the mother of F2 are brother and sister. No aneuploidy or deletion/duplication defects were detected by Whole-Genome SNP CNV analyses. WGNGS for all members, comparative genome analyses and data mining are as follows: [Only exonic variants considered, prioritized according to increasing population frequency (0–1%), damaging effects according to mutation prediction models and will be presented in table format]. 1. The two ASD events are unrelated and due to individual de-novo variants. Trio analyses for identified 36 de novo variants in F1 and 32 in F2. Variants in KCNH1, ANKRD36C, FRG2C, LOC12989375 were in common 2. The two ASD events are due to heterozygous variants inherited from the related parents. In F1, 370 father-to-son heterozygous variants, in F2, 398 mother-to-son heterozygous variants identified with 132 in common. 3. The related parents are protected from the damaging effects of ASD predisposing variants transmitted to their respective children by protective variants that were not transmitted, hence ASD in their offspring. Analyses were for heterozygous variants shared among the related parents but not transmitted to their affected children. 4. The non-related parents contributed rare predisposing variants, which in synergy with the inherited variants from the related parents exceed a disease onset threshold in the affected offspring. For F1 mother-to-son heterozygous variant transmission; For F2 father-to-son heterozygous variant transmission examined. Complex comparative genome analyses are required to decipher the genetic basis of ASD in families with multiple affected individuals. WGNGS, analyzed for the exome data, is a powerful tool for studying the genetic causes of ASD producing superior results than exome data in which other enrichment technologies are used. WGNGS, even when analyzed only for the exome data, provides clues to novel ASD risk genes, that can be pursued clinically, bioinformatically and functionally.

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/content/papers/10.5339/qfarc.2016.HBPP2407
2016-03-21
2020-10-25
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarc.2016.HBPP2407
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