Novel Unbalanced Translocations Affecting the Long Arms of Chromosomes 10 and 22 Cause Complex Syndromes with Very Severe Neurodevelopmental Delay, Speech Impairment, Autistic Behavior, and Epilepsy

Abstract

Isolated abnormalities in terminal regions of chromosomes 10q and 22q were formerly described in patients affected by neuropsychological impairment, abnormal facies, and heterogeneous structural abnormalities of the body. Chromosomes 10q and 22q harbor important genes that play a major role in CNS development, like DOCK1 and SHANK3, and in overall body growth, like FGFR2 and HTRA1. By using clinical, neuroradiological, neurophysiological, and genetic assessment, we studied 3 siblings affected by 2 different forms of very severe neuropsychological impairment with structural physical abnormalities, epilepsy, and body overgrowth. The genetic analysis revealed 2 different unbalanced translocations t(10;22)(q26.13;q13.32) of genetic material between the long arms of chromosomes 10 and 22, deriving from a maternal balanced translocation. Consequences of the unbalanced translocation were the simultaneous partial monosomy of 10q26.13 to 10qter and partial trisomy of 22q13.32 to 22qter in 2 patients and the simultaneous trisomy distal q10 and monosomy distal q22 in 1 patient, respectively. To the best of our knowledge, we here describe for the first time a causal association between an unbalanced translocation t(10;22) affecting the long arms of both chromosomes 10 and 22 and a very severe neurodevelopmental delay in 3 siblings.

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice

“…Notably, a microdeletion of the NEGR1 gene was described in two siblings that presented cognitive disabilities, ADHD, speech problems and features of autism in one of them ( Genovese et al , 2015 ). Moreover, gene-association studies have also implicated FGFR2 as a candidate gene in ASD ( Wentz et al , 2014 ; Coci et al , 2017 ). Interestingly, FGFR2 mutations are causative of syndromic intellectual disabilities, such as Crouzon syndrome ( Fernandes et al , 2016 ) and Apert syndrome whose patients may also suffer from ASD ( Morey-Canellas et al , 2003 ; Koca, 2016 ).…”

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration

“…Allen Developing Mouse Brain Atlas. Available from: http://developingmouse.brain-map.org/) and FGFRs have been associated with neurodevelopmental diseases including schizophrenia (O'Donovan et al, 2009; Terwisscha van Scheltinga et al, 2013), epilepsy (Coci et al, 2017; Okazaki et al, 2017), autism spectrum disorders (Wentz et al, 2014; Coci et al, 2017) and lissencephaly (Tan and Mankad, 2018), suggesting possible roles in neuron migration. However, analysis of cortical neuron migration in FGFR mutant mice has been inconclusive for two reasons.…”

Regulation of FGF10 Signaling in Development and Disease

“…More recently, chromosomal translocation and duplication events at the loci of the Fgf10 and Fgfr2 genes have been associated with neurological disorders such as developmental delay and autism ( Casey et al, 2012 ; Wentz et al, 2014 ). The role of single nucleotide polymorphisms and de novo point mutations causing oncogenic expression of Fgf10 and Fgfr2 are also becoming clearer, particularly in pancreatic, gastric, and breast cancers ( Jang et al, 2001 ; Theodorou et al, 2004 ; Nomura et al, 2008 ; Reintjes et al, 2013 ; Su et al, 2014 ; Sun et al, 2015 ; Ghoussaini et al, 2016 ; Coci et al, 2017 ). (D) FGF10-dependent activation of FGFR intracellular tyrosine residues (Y; insert), adaptor proteins (gray), protein kinases (red), and transcription factors (blue).…”