No, it is not mutually exclusive! A case report of a girl with two genetic diagnoses: Craniofrontonasal dysplasia and pontocerebellar hypoplasia type 1B

Abstract

Key Clinical MessageMultiple genetic disorders can coexist in one patient. When the phenotype is not fully explained with one diagnosis, it is recommended to perform further genetic investigations in search for coexisting second diagnosis.AbstractCraniofrontonasal dysplasia (CFND) (MIM: 304110) is an X‐linked dominant disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. It is caused by a pathogenic variant in EFNB1. Pontocerebellar hypoplasia type 1B (PCH1B) (MIM: 614678) is an extremely rare condition with over 100 individuals reported to date. It is caused by biallelic pathogenic variants in EXOSC3. This report presents the case of a girl who was diagnosed prenatally with CFND based on the findings on the prenatal imaging and the known diagnosis of CFND in her mother. She has severe global development delay that cannot be explained solely by the CFND diagnosis. Around the age of 2 years, she was diagnosed with PCH1B following whole exome sequencing (WES) testing. The objective of this study is to highlight the importance of pursuing genetic investigation if the available genetic diagnosis cannot fully explain the clinical picture. This is a case report of one patient and review of the literature. Informed consent was obtained from the parents. WES was performed by a private lab using next‐generation sequencing (NGS), DNA was sequenced on the NovaSeq 6000 using 2 × 150 bp paired‐end read. WES identified the following: homozygous pathogenic variant in EXOSC3: C.395A>C, p.ASp132Ala, maternally inherited, likely pathogenic duplication at Xq13.1 (includes EFNB1) and paternally inherited 16p11.2 duplication that is classified as a variant of uncertain significance. Perusing more extensive genetic testing like: WES is indicated if the current genetic diagnosis cannot fully explain the phenotype in a patient.