Rare and low frequency genomic variants impacting neuronal functions modify the Dup7q11.23 phenotype

Abstract

Background 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). Results We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance. Conclusions Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype.

Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse

“…Maestrini [13] Exonic Male 13-0577-003 ASD Exonic Male 15-0086-003 ASD Maestrini and Pagnamenta [13,39] Exonic Male 15-0084 ASD Maestrini [13] IMMP2L Linkage Paternal ASD Bertelsen et al, 2014 [40] Exonic Male ASD, GTS, ADHD, Asperger Zhang et al, 2017 [41] Exonic Male ASD, Speech Delay, Echo, MR Exonic Male ASD, Speech Delay, Echo, MR Exonic Male ASD, Speech Delay, Echo MR Gimelli et al, 2014 [42] Exonic Male Autistic, Speech Delay, ADHD Baldan 2018 [38] Intronic Male ASD, Speech Delay Exonic Male ASD, Speech Delay Leblond et al, 2019 [37] Exonic -ASD Qaiser et al, 2021 [46] Exonic -ASD Vinas-Jornet 2018 [45] Exonic -ASD…”

“…A ‘common chromosomal fragile site’ located within the IMMP2L gene [ 35 ] appears to contribute to the genes’ relative instability with high incidence of heterozygous deletions reported within IMMP2L in ASD and in normal ‘neurotypical’ populations ( Table 2 ) [ 36 ]. A number of smaller studies had suggested that IMMP2L may be deleted at higher frequencies in ASD [ 13 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Table 2 ), Gillies de la Tourette syndrome (GTS) [ 40 , 47 , 48 , 49 , 50 ], attention deficit hyperactivity disorder, (ADHD) [ 44 ] and intellectual disability (ID) [ 45 ] populations ( Table 3 ). Larger studies, however, indicate that the frequency of IMMP2L deletions (inclusive of exon sequence) in ‘neurotypical’ control populations is often higher (between 0.1% and 1.85%) [ 36 ] than those associated with ASD (between 0.27% and 1.54% [ 36 ]) and other neurodevelopmental disorders.…”

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox–Gastaut syndrome

“… 23 , 26 Ancestry and kinship analyses were carried out using PLINK (v1.9), as previously described. 27 …”

“…Rare SNVs and CNVs impacting both coding and non-coding regions of the genome were analysed, as previously described. 27 , 28 TR expansions were filtered based on the genomic content disrupted, biological relevance, known disease associations, and any overlap with reported literature or clinical reports in databases. Using the American College of Medical Genetics and Genomics’ (ACMG) guidelines, we classified rare SNVs and CNVs into pathogenic (i.e.…”