The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports

Abstract

Proximal 6q (6q11-q15) deletions are extremely rare and little is known about their phenotypic consequences. Since parents and caregivers now use social media to seek information on rare disorders, the Chromosome 6 Project has successfully collaborated with a Facebook group to collect data on individuals worldwide. Here we describe a cohort of 20 newly identified individuals and 25 literature cases with a proximal 6q deletion. Microarray results and phenotype data were reported directly by parents via a multilingual online questionnaire. This led to phenotype descriptions for five subregions of proximal 6q deletions; comparing the subgroups revealed that 6q11q14.1 deletions presented less severe clinical characteristics than 6q14.2q15 deletions. Gastroesophageal reflux, tracheo/laryngo/bronchomalacia, congenital heart defects, cerebral defects, seizures, and vision and respiratory problems were predominant in those with 6q14.2q15 deletions. Problems related to connective tissue (hypermobility, hernias and foot deformities) were predominantly seen in deletions including the COL12A1 gene (6q13). Congenital heart defects could be linked to deletions of MAP3K7 (6q15) or TBX18 (6q14.3). We further discuss the role of ten genes known or assumed to be related to developmental delay and/or autism (BAI3, RIMS1, KCNQ5, HTR1B, PHIP, SYNCRIP, HTR1E, ZNF292, AKIRIN2 and EPHA7). The most influential gene on the neurodevelopmental phenotype seems to be SYNCRIP (6q14.3), while deletions that include more than two of these genes led to more severe developmental delay. We demonstrate that approaching individuals via social media and collecting data directly from parents is a successful strategy, resulting in better information to counsel families.

A critical role for the nuclear protein Akirin2 in the formation of mammalian muscle in vivo

“…Together with prior studies in other cell types identifying Aki2 as a master regulator of gene expression, our data indicate that Aki2 controls the proper expression of key factors that drive mammalian myogenesis. Interestingly, a recent study reported that deletions in human chromosome 6q11‐15, which contains the Aki2 gene among several others, is associated with developmental delay, abnormal skull shape, dysplastic outer ear, and hypotonia (Engwerda et al, ), phenotypes potentially consistent with what we observe here and elsewhere (Bosch et al, ) in mice.…”

Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

“…On the other hand, patient 5 was found to have a paternally inherited variant of uncertain significance (VUS) (c.1762A>G;p.(I588V)) in the EFTUD2 gene (MIM *603892), which is associated with mandibulofacial dysostosis with microcephaly (MIM #610536) 25. This variant is reported in two out of 129 166 alleles in individuals of European background in GnomAD26 (accessed on March 29, 2019) and is predicted to be benign by PolyPhen27; therefore, it could be a rare benign variant. It is unclear if this variant is contributing to this patient’s phenotype and could explain his more severe presentation including microcephaly and dysmorphic features.…”

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

“…These variants in ZNF292 were associated with neurodevelopmental disorders with or without ASD [170]. Deletion of 6q14.3 in ZNF292 also resulted in ASD symptoms, such as learning and intellectual disabilities and behavioral problems [183].…”