Male-Biased Autosomal Effect of 16p13.11 Copy Number Variation in Neurodevelopmental Disorders

Abstract

Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a number of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy number variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59; p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females (OR = 1.19, p = 0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb genomic region between 15.49–16.32 Mb, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.

Two male adults with pathogenic AUTS2 variants, including a two-base pair deletion, further delineate the AUTS2 syndrome

“…(These items were selected because they occurred in at least two unrelated individuals with AUTS2 syndrome.) 1, [3][4][5][6][7][8][9][10][11] frameshift in the full-length AUTS2 transcript, likely to cause haploinsufficiency. Both men have intellectual disability, an autism spectrum disorder, feeding difficulties after birth, mild distal joint contractures and mild dysmorphic features.…”

Clinical utility gene card for: 16p13.11 microdeletion syndrome

“…[2][3][4][5][6][7][8][9][10][11][12] Interval II (chr16:15.48-16.32 Mb, GRCh37/hg19) represents the critical region of the genomic variation, being contained in the great majority of the 16p13.11 microdeletions identified so far. [2][3][4][5][6][7][8][9][10][11][12] It encompasses a core set of eight protein-coding genes, including NDE1, the strongest candidate gene for the neurodevelopmental phenotypes associated with the 16p13.11 microdeletions. NDE1 encodes the nuclear distribution protein nudE homolog 1, a centrosomal protein that has a crucial role in the process of mammalian encephalisation and human cerebral cortex growth.…”

“…16,17 Sequencing of the NDE1 gene and of the entire 16p13.11 homologous region of the intact chromosome in mentally retarded and epileptic patients carrying the heterozygous microdeletion, did not unmask any relevant recessive-acting mutation, which suggests that haploinsufficiency of one or more dosage-balanced genes included in the region represents one of the principal mechanisms responsible for the pathogenicity of the microdeletion. 4,8 Mutations published in the literature and mutations submitted without publication are available in a number of resources, including the BBGRE, DECIPHER and ISCA databases, 12,18,19 each holding genomic and associated phenotypic data from B5000, B26 000 and B32 000 phenotypically abnormal individuals, or the CHOP CNV and DGV databases, 20,21 holding CNV data derived from B2000 and B12 000 healthy individuals, respectively. By facilitating interactions between researchers, these international resources provide important tools for genetic research and medical care, aiding the understanding of genotype/ phenotype correlations and the identification of the diseasecausing genes, with consequent improvements in diagnosis, management and therapy for affected individuals.…”

“…The 16p13.11 microdeletions are pleiotropic genomic variants with broad phenotypic manifestations, including neurodevelopmental phenotypes such as autism, mental retardation, epilepsy and learning difficulties and non-CNS phenotypes such as physical dysmorphisms and congenital anomalies. [2][3][4][5][6][7][8][9][10][11][12] This variable phenotypic expressivity represents a challenge for clinical diagnosis because similar clinical features have been associated with a number of other genomic variations (eg, del1q21.1 or del15q11.2), and a characteristic common phenotype for the 16p13.11 microdeletion carriers has not yet been identified. Furthermore, clinical diagnosis can also be hampered by the presence of 'second-hits', additional pathogenic variations in other genomic regions that act in concert with the 16p13.11 microdeletions, and are able to exacerbate or mask some of their phenotypic symptoms.…”

“…The microdeletion generally shows incomplete penetrance, with some of the carriers being completely unaffected, also within high-risk families. 4,6,7,12 …”