Ancient Haplotypes at the 15q24.2 Microdeletion Region Are Linked to Brain Expression of MAN2C1 and Children's Intelligence

Abstract

The chromosome bands 15q24.1-15q24.3 contain a complex region with numerous segmental duplications that predispose to regional microduplications and microdeletions, both of which have been linked to intellectual disability, speech delay and autistic features. The region may also harbour common inversion polymorphisms whose functional and phenotypic manifestations are unknown. Using single nucleotide polymorphism (SNP) data, we detected four large contiguous haplotype-genotypes at 15q24 with Mendelian inheritance in 2,562 trios, African origin, high population stratification and reduced recombination rates. Although the haplotype-genotypes have been most likely generated by decreased or absent recombination among them, we could not confirm that they were the product of inversion polymorphisms in the region. One of the blocks was composed of three haplotype-genotypes (N1a, N1b and N2), which significantly correlated with intelligence quotient (IQ) in 2,735 children of European ancestry from three independent population cohorts. Homozygosity for N2 was associated with lower verbal IQ (2.4-point loss, p-value = 0.01), while homozygosity for N1b was associated with 3.2-point loss in non-verbal IQ (p-value = 0.0006). The three alleles strongly correlated with expression levels of MAN2C1 and SNUPN in blood and brain. Homozygosity for N2 correlated with over-expression of MAN2C1 over many brain areas but the occipital cortex where N1b homozygous highly under-expressed. Our population-based analyses suggest that MAN2C1 may contribute to the verbal difficulties observed in microduplications and to the intellectual disability of microdeletion syndromes, whose characteristic dosage increment and removal may affect different brain areas.

Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder

“…Cortical layer V neurons were degenerated with vacuoles, and white matter lesions characterized by vacuolated oligodendral cells were abundant. 25 Vacuolization was not observed on brain histology of individuals 3 and 4 at approximately 30 weeks gestation. However, it is not excluded this might be a feature appearing later in life.…”

“…A few studies have already highlighted the importance of MAN2C1 independently of its mannosidase catalytic function in tumorigenesis and malignant transformation. 25 For example, upregulation of MAN2C1 was observed in human prostate cancer cells, where MAN2C1 seemed to attenuate PTEN functions by binding to it. 23 It is conceivable that some part of the observed clinical phenotype could originate from PTEN dysfunction.…”

“… 24 Furthermore, a population-based analysis, which studied ancient haplotypes at the 15q24.2 microdeletion region, suggests that MAN2C1 variants may contribute to speech delay and intellectual disability. 25 To date, no other disorder or individual with pathogenic variants in MAN2C1 has been reported.…”

Discovery of eQTL Alleles Associated with Autism Spectrum Disorder: A Case–Control Study

“…CES1, a drug metabolizer, has been shown to have significantly different mRNA levels in peripheral leukocytes of ASD-affected individuals and unrelated ASD-unaffected mothers of ASD-affected individuals, compared to controls (Johnson et al, 2013 ; Kuwano et al, 2011 ). Microdeletions in the area surrounding MAN2C1 have been linked to gene expression of MAN2C1 in the brain, a lower verbal and non-verbal IQ, and ASD (Cáceres et al, 2016 ; McInnes et al, 2010 ; Roetzer et al, 2010 ).…”

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“…studies demonstrate that changes in copy number in the region have been implicated in autism and intellectual disability 28 .…”