MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus

Abstract

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms “mental retardation”. To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

Nine newly identified individuals refine the phenotype associated with MYT1L mutations

“…Only three of the nine individuals developed overweight/obesity postnatally. Thus, the frequency for overweight/obesity among these novel individuals is lower than reported before with 33% as compared to, for example, the 85% reported earlier (Blanchet et al, ). Severe congenital malformations were absent and craniofacial dysmorphism was generally mild.…”

“…One important example is overweight or obesity which affected all reported individuals with microdeletions affecting MYT1L in the first review, (Stevens et al, ). De Rocker et al found overweight/obesity of childhood onset in 71% of their deletion patients and both of their SNV patients (De Rocker et al, ) and Blanchet and colleagues in 85% of their novel and reviewed patients (Blanchet et al, ). However, only three out of the nine novel individuals presented here were affected.…”

“…A further case report described an individual with a de novo intragenic deletion of MYT1L and DD, microcephaly, behavioral problems, and stereotypies, but without obesity at an age of 4.5 years (Mayo et al, ). In 2017, Blanchet and colleagues published the next larger series of novel patients with ID/DD, reviewed the clinical phenotype and compared the clinical pictures of SNV mutation carriers with that of microdeletion carriers (Blanchet et al, ). In addition to one individual with a microdeletion, nine individuals with de novo MYT1L SNVs were reported.…”

“…MYT1L has been shown to be the main causative gene in such submicroscopic deletions of chromosome band 2p25.3 (Blanchet et al, ; De Rocker et al, ). A previous comparison of individuals with MYT1L deletion versus MYT1L SNVs identified no significant difference regarding the main clinical features (Blanchet et al, ).…”

Movement Disorders in Adults with 22q11 Deletion Syndrome

“…Chromosome microdeletions frequently cause disease through haploinsufficiency for genes in the deletion region (or deletion of genes at the breakpoint). 3,4 There are several interesting candidates within the 22q11 deletion involved in dopamine metabolism, mitochondrial function, or microRNA processing. To my knowledge, no single nucleotide variants in any of these candidate genes have been reported in PD cases.…”