Expanding the prenatal and postnatal phenotype spectrum of HEATR5B-related disorders

Biallelic hypomorphic variants in HEATR5B were first reported in four individuals from two families with pontocerebellar hypoplasia, but no disease entity is listed for HEATR5B in OMIM, Mondo or similar databases; despite its ubiquitous expression across multiple organ systems, the gene-disease relationship remains limited to neurodevelopmental disorders. Genematching between 2021 and 2026, lead to the identification of 12 novel variants in HEATR5B , from 17 individuals in 11 unpublished families. Eight of these families showed autosomal recessive inheritance (seven homozygous, one compound heterozygous), while the remaining three carried de novo variants. Stillbirth and fetal hydrops were observed in 5/8 and 7/8 individuals respectively, and neurological phenotypes accounted for 10/14 of the postnatal cases; other organ systems, including genitourinary, cardiac, digestive and respiratory, were less frequently affected. This is the largest HEATR5B cohort to date, and highlights the perinatal lethality of HEATR5B -related disorders, and its multiorgan systemic involvement beyond neurodevelopmental disorders alone.