Chromodomain Helicase DNA-Binding Domain 8 (CHD8) related neurodevelopmental disorder with overgrowth: a case series and a systematic literature review on neuroradiological findings

Purpose/Methods Chromodomain Helicase DNA-Binding Domain 8 (CHD8)-Related Neurodevelopmental Disorder with Overgrowth is a rare disorder, with approximately 120 cases reported to date. First, we report six cases that presented to our hospitals with intellectual disability, autism spectrum disorder and overgrowth and one related person. Second, we performed a systematic review on neuroradiological findings in people with CHD8 variants and people with submicroscopic abnormalities of the chromosomal region 14q11.2 that includes the CHD8 gene. Results Patient 1 carried a heterozygous pathogenic frameshift variant in CHD8: c.3638del, p.Gly1213Aspfs*40. Patient 2 harbors a heterozygous pathogenic missense variant in CHD8: c.5488 C > T, p.Arg1830Cys). In Patient 3 and 4 (mother and daughter) a heterozygous frameshift variant c.3343del, p.Ala1115Leufs*39 was identified and classified as variant of unknown significance (class 3). In Patient 5 we detected a splice variant in CHD8: c.2486 + 1G > A, p.? (class 4) and patient 6 carries the stop gain variant c.1540G > T, p.Glu514* (class 5). In patient 7 we found another missense variant in CHD8: c.3289 C > G, p.His1097Asp (class 4). Magnetic resonance imaging (MRI) of patients 1 and 2 revealed bilateral T2 hyperintense white matter signal alterations periventricular, in the u fibers and the deep white matter. MRI of patients 2, 5, 6 and 7 showed prominent perivascular spaces. Additionally, patients 3, 4, 5 and 6 had asymmetric low-lying cerebellar tonsils. In the systematic review, 16 of the 111 studies screened were included in the analysis. In total, neuroradiological imaging including MRI, computer tomography and ultrasound was described in 32 patients with CHD8 variants. Peculiarities were reported in 62.5% of the patients. The neuroradiological findings were highly variable, ranging from supratentorial white matter abnormalities to cerebellar findings and ventriculomegaly. Conclusions CHD8-Related Neurodevelopmental Disorder with Overgrowth can lead to various supra- and infratentorial neuroradiological findings.