Résumé
Neurodevelopmental and multiple malformation disorders spanning large phenotypic series can often lead to obscure diagnoses in the clinic. Blended phenotypes from multiple etiologies can compound this issue. We present a rare familial case of two siblings with Nicolaides-Baraitser syndrome (NCBRS) complicated by an initial diagnosis of syndromic craniosynostosis in one of the patients. Case Presentation: Whole exome sequencing (WES) was performed for the affected siblings using the Agilent SureSelect kit and Illumina HiSeq 2500 system, followed by GATK variant calling and in-house annotation. Sanger sequencing was used to validate candidate variants in all immediate family members. A pathogenic de novo variant in TCF12 (p.Gln646Ter), consistent with craniosynostosis type 3 (CRS3), was identified in the proband, along with a novel likely pathogenic variant in SMARCA2 (p.Ile833Phe) involved in NCBRS. The latter was also detected in the sister and is thus suspected to have arisen through germline mosaicism. Various overlapping phenotypic manifestations complicated clinical diagnosis. Conclusion: This case expands the molecular and clinical spectrum of NCBRS and CRS3 and underscores the utility of trio-based WES in detecting blended phenotypes of disorders with growing phenotypic spectrums. Paternal germline mosaicism may underlie high recurrence and inform reproductive counseling.