ZMYND11-related syndromic intellectual disability diagnosis in a case with classic Cornelia de Lange syndrome phenotype

We present the case of a 14-year-old male, child of non-consanguineous Brazilian parents, with classic Cornelia de Lange syndrome (CdLS) phenotype. He presents typical CdLS facial dysmorphisms, microcephaly, hirsutism, myopia, cardiac anomaly, hand oligodactyly and adactyly, cryptorchidism, cutis marmorata, pre- and postnatal growth retardation, global developmental delay, and intellectual disability. He also exhibits gastroesophageal reflux (GERD) and epilepsy. He required hospitalization due to pneumonia and orchiopexy surgery. He can speak a few words and has behavioral difficulties (tantrums and self-harm behavior). Whole-exome sequencing (WES) from peripheral blood revealed a pathogenic heterozygous variant in the ZMYND11 gene (Aoi et al. 2019, 10.1038/s10038-019-0643-z), associated with intellectual developmental disorder, autosomal dominant 30 (MRD30). Due to the patient’s classic CdLS phenotype, WES from buccal cells was also performed for mosaicism investigation in CdLS-associated genes, but no clinically relevant variants were identified. MRD30 and CdLS have phenotypic heterogeneity, and the patient exhibits phenotypic traits common to both syndromes, such as synophrys, thick eyebrows, thin upper lip, epilepsy, global developmental delay, intellectual disability, speech delay, and behavioral difficulties. However, hypertelorism and wide mouth, frequently observed in MRD30-affected individuals, are absent in the patient. Skeletal abnormalities are also described in both syndromes; however, in MRD30 patients, they are usually not as severe as those observed in our patient. Moreover, MRD30 patients usually have normal height, whereas growth delay is common among CdLS patients. Finally, our patient has GERD, which is common among CdLS patients, and can also be associated with feeding difficulties, which are frequently observed in MRD30 patients. In summary, while the ZMYND11 pathogenic variant explains part of the patient’s clinical features, he also presents phenotypes that are not described in MRD30 but are well established in CdLS. These findings suggest that this patient may have an atypical MRD30 phenotype or a dual diagnosis, potentially involving a CdLS-associated variant not detected with the current testing approaches.