The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role forDLL1

Abstract

Background: Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals. Results: Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1. Larger deletions that include QKI (>7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics. Conclusions: Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (>500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

Parent-reported phenotype data on chromosome 6 aberrations collected via an online questionnaire: data consistency and data availability

“…In the parent cohort, data on sleeping problems was available for 33 out of 34 individuals but was available for only 2 out of 39 individuals in the literature cohort. Notably, 50% of individuals with a terminal 6q deletion were reported to suffer from sleeping problems, which can be a major burden to parents 4 .…”

“…These multiple-answer options were considered as one answer for this question and defined as partly (in)consistent if one part of the given answers was consistent and another inconsistent. Answers to sub-questions on developmental delay included IQ test scores and age of achievement for developmental milestones, with the latter converted to developmental quotients (DQ) as described previously 4 . The IQ test scores and DQs were categorized as normal (>85), borderline (70–85), mild (50–70), moderate (30–50) or severe (<30) delay.…”

“…Data collected on individuals with terminal 6q deletions was used for the data availability study. Individuals were selected from the Chromosome 6 Project and from literature using previously described criteria 2,4 plus two additional criteria: foetuses and new-borns were excluded and only index cases (or the person best-described in the case report) were included. The Chromosome 6 Questionnaire was completed by parents for their child and by a researcher of the Chromosome 6 Project for the literature cases.…”

“…More details are provided in Engwerda et al 2022. 4 Data analysis Data was classified as available (feature present or absent) or unavailable (feature unknown or missing). For follow-up, growth measurement data was classified as available when at least one measurement was available.…”

“…Notable p-values of data availability for main and sub-questions For the main question on developmental delay, only individuals above the age of 2 years were included (see methods in Engwerda, et al 2022)4 .…”