Identification of Novel Co-Occurring ZNF711 and SRCAP Variants in a Child with Neurodevelopmental Disorders Through Exome Sequencing.

BACKGROUND: Global developmental delay (GDD)/intellectual disability (ID) represent a group of neurodevelopmental disorders (NDDs) with onset in childhood with a global prevalence of 1-3%. The etiology of GDD/ID is complex, with genetic factors accounting for about half of cases. Exome sequencing (ES) has proven to be an effective diagnostic tool for genetically heterogeneous disorders such as GDD/ID. This study aims to identify the genetic etiologies using ES in a Chinese patient with NDD. METHODS: Clinical data were collected through physical examination. Trio-ES was conducted to investigate the potential genetic causes, followed by Sanger sequencing for validation. RESULTS: The proband exhibited facial dysmorphisms, motor and language development delay, ID, autism spectrum disorder, and attention-deficit hyperactivity disorder symptoms. Trio-ES identified a novel maternal inherited hemizygous nonsense variant c.205G>T (p.E69*) in ZNF711, and a novel de novo missense variant c.673C>T (p.R225C) in SRCAP. Both of variants were classified as likely pathogenic. Phenotype dissection revealed ZNF711 dominated neurodevelopmental abnormalities (Intellectual developmental disorder, X-linked 97, XLID97) and SRCAP contributed to multisystemic manifestations (developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, DEHMBA). CONCLUSION: To our knowledge, this study reports the first case of concurrent ZNF711 and SRCAP variants in China, expanding variant spectrum of both genes. It highlights the critical value of ES for detecting multi-gene variants in probands with complex phenotypes.