Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31

Abstract

We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning.

Homozygous Missense Variation in <b><i>PNPLA8</i></b> Causes Prenatal-Onset Severe Neurodegeneration

“…While most members of PNPLA family (PNPLA2, PNPLA3, PNPLA5, and PNPLA7) have their role in lipid storage and metabolism [Fischer et al, 2007;Reilich et al, 2011;Mikhailova et al, 2019;Pingitore and Romeo, 2019;Wang et al, 2020], PNPLA1 is associated with congenital ichthyosis (OMIM #612121). Labonne et al [2020] recently proposed PNPLA4 as likely genes for X-linked in- Our patient harbored a missense variant in the patatin domain of PNPLA8. All 3 previously reported patients had truncating variations that lie outside this domain (Fig.…”

Lipolysis: cellular mechanisms for lipid mobilization from fat stores

“…Similar to PNPLA3, various enzymatic activities have been attributed to PNPLA4, including TG and retinyl ester hydrolase, phospholipase and transacylase activities 8,225,226 . Genetic analyses have suggested that PNPLA4 is involved in the development of two rare congenital disorders: combined oxidative phosphorylation deficiency (COXPD) and X-linked intellectual disability 227,228 . COXPD arises from a hemizygous nonsense mutation resulting in a C-terminally-truncated protein (R187ter) and defective assembly of complexes I, III and IV of the respiratory electron transport chain.…”

Gene Set Enrichment Analysis of Interaction Networks Weighted by Node Centrality

“…However, its centrality is low in patient 1 (C B = 7.56 × 10 –3 ), whereas it has the top value in the other three patients. Recently, a role for LRRK2 in cognitive development has been proposed, thus linking LRRK2 to intellectual disability and autism ( Labonne et al, 2020 ). Another gene present with very high centrality in all four networks, ESR1 , has been related to the pathogenesis of autism and autism related symptoms ( Wang et al, 2016 ).…”