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.

Fig. 1

Overview of all proximal 6q deletions. Deletions in the region of 6q11-q15 are shown for our parent cohort (black bar) and literature cohort (grey bar), and are divided into five subgroups (A–R). A: deletions of 6q11q13 extending proximally to 72.5 Mb (calculated from 6pter); B: deletions of 6q13q14.1 in the region 72.5–84.5 Mb; C: deletions of 6q14.2q14.3 in the region 81–88.5 Mb; and D: larger deletions of 6q14.2q15 extending from 81–95 Mb. Deletions in subgroup (R) were large deletions of 6q12q15 overlapping with two or more of the other subgroups A–D. The deletions are visualised using the UCSC genome browser (https://genome.ucsc.edu). Patient Id116 also has a partial duplication of 6q14.1 (indicated by a white bar). The literature cases were derived from 13 reports [–19]. See supplementary Table S1 for details

Fig. 2

Clinical photographs of individuals with a proximal 6q deletion. Photographs of patients in subgroups A–D. Subgroup A: patient Id123 (A1) at age 22 months, patient Id065 (A2) at age 7 years, patient Id057 (A3) at age 18 months. Subgroup B: patient Id058 (B1) at age 8 years, patient Id019 (B2) at age 7 years, patient Id011 (B3) at age 5 years. Subgroup C: patient Id125 (C1) at age 2; 11 years, patient Id028 (C2) at age 8 years, patient Id056 (C3) at age 2; 5 years. Subgroup D: patient Id007 (D1) at age 8 years, patient Id044 (D2) at age 3 years, patient Id067 (D3) at age 22 years. Written consent was given to the authors to publish the patients’ photos

Fig. 3

Age of achievement for the milestones ‘walking independently’ and ‘using two-word sentences’. The light grey bars indicate the number of children (x axis) that have reached the milestones ‘walking independently’ (upper panel) and ‘using two-word sentences’ (lower panel) before the given age (y axis). The dark grey bars are the children who were not able to perform the milestones at that age. The hatched bars are children who were not able to perform the milestone, but who have not yet reached the age on the y axis. For example, at age 12 years, 66–97% of the children are able to walk. Only children older than 12 months and for whom information is available were included here.

Fig. 4

Phenotype–genotype map of proximal chromosome 6q. An idiogram of proximal 6q is shown: genes with a known or likely phenotypic effect and an HI score <10% or a pLI score >0.9 are shown on the left. Genes printed in italics have a higher HI% or lower pLI, but are discussed in the text as being related to autism. On the right-hand side, the critical regions for various clinical features are indicated