Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Lia D’abate ,Janet A Buchanan ,Susan E Bryson ,Zachary Warren ,Karen R Dobkins ,Sally J Ozonoff ,Gregory S Young ,Jonathan Leef ,Kristiina Tammimies ,Susan Walker ,John Wei ,Lonnie Zwaigenbaum ,Isabel M Smith ,Daniel S Messinger ,Ryan K C Yuen ,Jessica Brian ,Wendy L Stone ,Jennifer Howe ,Robbie Davies ,Bhooma Thiruvahindrapuram ,Rebecca Landa ,Stephen W Scherer

doi:10.1038/s41467-019-13380-2

Abstract

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Highlights

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD
In search of biomarkers for early indentification, we investigated whether copy number variants (CNVs) affecting ASD-related loci correlate with phenotypic outcomes in the Baby Siblings Research Consortium (BSRC) cohort of infant siblings whose family history is associated with a higher probability of developing ASD (Fig. 1)
Identification of the CNVs described in this study could be used to tailor recurrence risk estimates to individual families, with potential for intensified surveillance for infants at increased likelihood due to positive CNV findings

Summary

Introduction

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. We describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically. In search of biomarkers for early indentification, we investigated whether CNVs affecting ASD-related loci correlate (pre- and post-symptomatically) with phenotypic outcomes in the Baby Siblings Research Consortium (BSRC) cohort of infant siblings whose family history is associated with a higher probability of developing ASD (Fig. 1). Our analyses reveal that the detection of ASD-relevant CNVs is predictive of ASD or atypical development in this sibling population and can be used to inform risk estimates for individuals and their families, with potential impact on their therapeutic trajectory

Methods

Results

Conclusion