Expanding the clinical and molecular spectrum of SETD5, NEDD4L, and TBL1X related disorders: A case report and literature review.
TL;DR
To the authors' knowledge, this is the first report of such a unique overlap, highlighting the importance of considering multilocus genomic variation in heterogeneous neurodevelopmental presentations.
Abstract
We report a unique clinical case of a male child presenting with a blended phenotype characterized by intellectual disability, seizures, periventricular nodular heterotopia (PVNH), congenital central hypothyroidism, and multiorgan malformations. Exome sequencing (ES) identified three rare variants: a de novo frameshift variant in SETD5 (g.3-9441593 ;NM_001080517.3:c.812dup; p.(Leu271PhefsTer42)), a de novo missense variant in the WW domain of NEDD4L (NM_015277.6:c.1525C > T; p.(Arg529Cys)), and a maternally inherited nonsense variant in TBL1X (X-9711651-C-T) (NM_005647.4:c.1480C > T; p.(Arg494Ter)). While the likely pathogenic SETD5 and TBL1X variants are consistent with the neurodevelopmental delay and central hypothyroidism respectively, the NEDD4L variant of uncertain significance (VUS) represents a plausible candidate for the PVNH. To our knowledge, this is the first report of such a unique overlap, highlighting the importance of considering multilocus genomic variation in heterogeneous neurodevelopmental presentations.