Further delinaeation of phenotypes in RAD21
Aberrations in RAD21 (RAD21 Cohesin Complex Component) have been associated with clinical phenotypes that overlap with that of Cornelia de Lange Syndrome (CdLS)1.
Although it has been stated that RAD21 variants lead to a relatively mild CdLS phenotype, the number of reported individuals on which this has been based is small, and insight into the cognitive and behavioral aspects is limited(1).
We aimed to provide a complete overview of the RAD21 variants reported thus far, and to gather the associated phenotype data with a special focus on development, cognition and behavior.
Using international inquiry, literature and database search, we identified 53 cases from 37 families in which the phenotype could be reliably attributed to RAD21 (including patients with microdeletions, microduplications, heterozygous and homozygous sequence variants of RAD21). These were diagnosed through targeted as well as non-targeted genetic approaches. We performed in silico analyses of the effect of all sequence variants on the protein level.
With a dedicated questionnaire, we gathered extensive and updated molecular, clinical, developmental, cognitive and behavioral data, which allowed for deep phenotyping in a core cohort of 29 patients out of 22 families (24 with sequence variants, and 5 with small microdeletions encompassing RAD21) . We compared the phenotype of these 29 patients to that of CdLS patients with variants in NIPBL (n=67) and SMC1A (n=51)2 3, and investigated genotype-phenotype relationships.
All 29 patients in the core cohort had such number of features of CdLS that this was sufficient to warrant molecular genetic testing for CdLS; 13 met clinical criteria for classical CdLS, and 12 for non-classical CdLS. Overall, somatic, cognitive and behavioral problems were markedly less prevalent and, if present, less severe, in RAD21 cases compared to the patients in the NIPBL and SMC1A cohorts. Still, impairments in most CdLS associated areas were found, and even without intellectual disability patients tend to have subtle problems in development, cognition and behavior. Remarkable findings, differing from patients with NIPBL or SMC1A variants include a paucity of self-injurious behavior and apparent absence of major limb malformations in our patient group.
The core cohort included 2 recurrent mutations each in 2 families, without clear differences in phenotypes; further genotype-phenotype analyses are in progress and will be presented at the meeting. Exploration of six families with multiple affected family members demonstrated a marked intrafamilial variation, with part of the patients only identified after diagnosis in a child or sib. The major differences within affected members in a family have obvious consequences for counseling.
This case series represents a comprehensive overview of all RAD21 sequence variants reported so far, and 21 new index cases. The data should be of benefit to physicians when counseling families with affected members with a RAD21 variation.
Conflicts of interest: none.
- references;
- ^ Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, et al. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nat Rev Genet. 2018;19(10):649-66.
- ^ Huisman S, Mulder PA, Redeker E, Bader I, Bisgaard AM, Brooks A, et al. Phenotypes and genotypes in individuals with SMC1A variants. Am J Med Genet A. 2017;173(8):2108-25.
- ^ Mulder PA, Huisman S, Landlust AM, Moss J, Consortium SA, Piening S, et al. Development, behaviour and autism in individuals with SMC1A variants. J Child Psychol Psychiatry. 2019;60(3):305-13.
CdLSWorld Conference 2019, Germany and Netherlands, Ahrweiler, published on 31 Jul 2019
