Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

Abstract

Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (<i>ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205</i> and <i>ZEB2</i>). Using simulation models, we showed that five genes (<i>DLG4, NFIX, EHMT1, ZEB2</i> and <i>ATP1A1</i>) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including <i>NSD1</i> and <i>NFIX</i>, which are known to be mutated in overgrowth syndromes. We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10^-4) and genes regulated by the fragile X mental retardation protein (p=3×10^-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.