Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)