Editors' ChoiceAutism

Autism heritability: A new twist on familial genetics?

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Science Translational Medicine  25 Feb 2015:
Vol. 7, Issue 276, pp. 276ec32
DOI: 10.1126/scitranslmed.aaa8329

Autism spectrum disorder (ASD) is a common neurodevelopmental condition associated with substantial morbidity. Its pathogenesis remains poorly understood, and available treatments are mainly supportive. A genetic basis for ASD has long been suspected based on investigations of affected twins and multiplex kindreds. In recent years, next-generation sequencing (NGS) studies led to the identification of hundreds of ASD-risk genes; not surprisingly, many are implicated in brain functions. Now, using whole-genome sequencing (WGS), Yuen and colleagues reveal that many siblings with ASD have nonoverlapping sets of mutations in ASD-risk genes.

This study addresses questions raised by prior reports suggesting that genetic heterogeneity among siblings affected by ASD is underappreciated. High-quality WGS data were obtained for all individuals from 85 kindreds, each with two affected siblings and unaffected parents. Using standard algorithms to filter genetic variations, mutations likely to contribute to ASD were identified in ~40% (36 of 85) of families. Genes were assigned to 4 classes of ASD-risk genes based on level of evidence of association: confirmed (8 families), candidate (10), putative (10), and observed in other neurodevelopmental disorders (NDD; 8). Of utmost interest is the fact that siblings with concordant genotypes predicted to be pathogenic were found in only 11 of 36 families. The other key finding is that siblings with discordant genotypes were more likely to exhibit heterogeneous ASD-related phenotypes.

These results challenge the notion that familial genetic diseases are invariably caused by mutation in the same gene. If this new framework is correct (and not ASD-specific), the size of the search space for traditional family-based gene discovery studies may need to be widened, especially when first-pass analyses do not identify co-segregating mutations. This study has two notable limitations. First, it is best to use clear-cut data when challenging established dogma: In this case, it may have been preferable to exclude genes from classes with as yet unresolved links to ASD (such as “putative” or “NDD”) from the analysis, and to use a larger number of quartets to increase statistical power. Second, the automatic classification of any de novo variants as de facto pathogenic may have biased the analysis, because these variants are expected to recur only rarely in siblings (due to gonadal mosaicism). As expected, of the 15 of 36 families who had de novo variants, 14 of 15 were discordant. Independent corroboration in larger cohorts will be required to determine whether this hypothesis is indeed a “game changer.”

R. K. C. Yuen et al., Whole-genome sequencing of quartet families with autism spectrum disorder. Nat. Med. 21, 185–191 (2015). [Abstract]

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