Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders

Abstract

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance ( P < 3.64e–7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense ( n = 41) or truncating ( n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden ( DDX3X , MECP2 , WDR45 , and HDAC8) . This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

CTNNB1 in neurodevelopmental disorders

“…In the latest release of whole-genome sequencing (WGS) data from the Autism Speaks MSSNG resource ( https://research.mss.ng , 5,100 individuals with ASD and 6,212 non-ASD parents and siblings), CTNNB1 (FDR 0.001 to 0.0001) was further identified as one of the 134 ASD-associated genes ( 54 ). Based on another single-cell nuclei transcriptomic data ( 55 ), 615 NDDs candidate genes (FDR < 0.05) had been identified and CTNNB1 was recognized as high-risk ASD genes in 46,612 trios by de novo enrichment analysis. CTNNB1 is identified as a category 1 gene (strong candidate ASD gene) according to the Simons Foundation Autism Research Initiative (SFARI) database.…”

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

“…The top 10 most prevalent DNV among GDD/ID are listed in Table 1 [ 2 ]. Most of the GDD/ID genes discovered were de novo variants (DNV) [ 2 , 8 , 13 , 14 ]. Deletions were more common than duplications, resulting in frameshift, stop-gained, alternative-splice-site, or missense mutations.…”

“…Some of the X-linked ID genes exhibit skewed inactivation and incomplete penetration, resulting in varying degrees of clinical phenotypes in females [ 17 ]. ID genes with female-biased burdens and extreme skewing that have been identified to date include DDX3X , MECP2 , WDR45 , SMC1A , HDAC8 , and NHS [ 13 , 17 ].…”

Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism

“…Autism is a devastating condition, diagnosed in early childhood and characterized by qualitative impairments in social interaction and communication skills, accompanied by repetitive and stereotypic behaviors and interests [ 1 ]. Interestingly, recent advances in next-generation sequencing allowed large-scale exome sequencing initiatives revealing identification of a large series of genes involved in the disorder [ 2 – 4 ]. While collectively common, mutations in individual genes are rare and, in many cases, only a handful of patients with mutations in any specific gene are identified.…”

“…In this review, we discuss the multiple chromatin remodeling properties of the Activity-Dependent Neuroprotective Protein (ADNP) [ 9 ]. The ADNP gene has been found to be mutated in significant percentage of patients diagnosed with syndromic autism or intellectual disability and is one of its more frequent genetic causes [ 2 – 4 , 10 ]. With the expansion of recent studies on the ADNP gene and its role in development, a comprehensive review of the function with emphasis on chromatin remodeling is warranted.…”