A Novel Variant in RAD21 in Cornelia De Lange Syndrome Type 4: Case Report and Bioinformatic Analysis

Abstract

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder that affects many organs. The diagnosis of this condition is primarily clinical and it can be confirmed by molecular analysis of the genes known to cause this disease, although about 30% of CdLS patients are without a genetic diagnosis. Here we report clinical and genetic findings of a patient with CdLS type 4, a syndrome of which the clinical features of only 30 patients have been previously described in the literature. The index patient presented with clinical characteristics previously associated with CdLS type 4 (short nose, thick eyebrow, global development delay, synophrys, microcephaly, weight < 2DS, small hands, height < 2DS). She also presented cardiac anomalies, cleft palate and laryngomalacia, which was never described before. The index patient was diagnosed with a novel de novo RAD21 variant (c.1722_1723delTG, p.Gly575SerfsTer2): segregation analysis, bioinformatic analysis, population data and in silico structural modelling indicate the pathogenicity of the novel variant. This report summarizes previously reported clinical manifestations of CdLS type 4 but also highlights new clinical symptoms, which will aid correct counselling of future CdLS type 4 cases.

History and highlights of the teratological collection in theNarrenturm, Vienna (Austria)

“…Its distinctive facial characteristics indicate a more complex syndromic phenotype: dysmorphisms include a low anterior hairline, synophrys and long bushy eyelashes (both slightly masked by discoloring after fixation), a long and smooth philtrum, thin vermilion of the upper lip with downturned corners of the mouth and micrognathia. Based on the classic facial appearance and the presence of severe reduction defects (peromelia and oligodactyly) of the upper limbs, we diagnosed this specimen as being affected by autosomal dominant Cornelia de Lange syndrome type 1 (OMIM 122470), since other types of Cornelia de Lange syndrome (OMIM 610759, 614701, 300590, 300882) are not described to be associated with oligodactyly (Allanson et al, 1997; Cascella & Muzio, 2021; De Falco et al, 2023; Kline et al, 2018). The red discoloration of the hair resulted from the acidified preservation fluid.…”

“…This specimen concerns a skeleton of a 25-year-old male who died in 1909 (Figure 10). 300590,300882) are not described to be associated with oligodactyly (Allanson et al, 1997;Cascella & Muzio, 2021;De Falco et al, 2023;Kline et al, 2018). The red discoloration of the hair resulted from the acidified preservation fluid.…”

Advancing the Clinical and Molecular Understanding of Cornelia de Lange Syndrome: A Multidisciplinary Pediatric Case Series and Review of the Literature

“…De Falco and colleagues docu-mented novel clinical manifestations associated with a mutation in the RAD21 gene. The index patient exhibited classic signs of Cornelia de Lange syndrome type 4, as well as previously unreported features such as cardiac anomalies, a cleft palate, and laryngomalacia [63].…”