Biallelic germline variants in the hematologic malignancy predisposition gene DDX41 cause retinal dystrophy through dysregulation of retinal homeostasis

DDX41

Biallelic germline loss-of-function DDX41 variants (DEAD-box RNA helicase): reduced protein expression, impaired RNA interaction through misfolding or non-productive aggregates, dysregulated Müller cell gene networks

Eight families with Leber congenital amaurosis or early-onset severe retinal dystrophy carry a biallelic combination of six germline DDX41 variants; DDX41 encodes a DEAD-box RNA helicase involved in RNA splicing, innate immunity and hematopoiesis. Protein expression is decreased in fibroblasts from a patient homozygous for the c.1187T>C (p.Ile396Thr) missense variant and in the retina of Ddx41 I396T/I396T knock-in mice, whose electroretinograms show visual dysfunction from the first month of age. Biochemical assays indicate that the variants disrupt DDX41 interactions with RNA through misfolding or non-productive aggregates, resulting in loss of function. Transcriptomic profiling of mutant retinas points to Müller cells as the site of dysfunction, with widespread architectural disruption. This is a medRxiv preprint, not yet peer-reviewed.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

First link between DDX41, known as a hematologic malignancy predisposition gene, and an early-onset recessive retinal dystrophy, supported by eight families, a knock-in mouse model and biochemical data. For geneticists, the open question is counseling of heterozygous parents and relatives, since monoallelic DDX41 variants confer myeloid predisposition: whether the retinal variants carry that risk is unknown, and the preprint does not address it. The peer-reviewed version should be read before setting any management.

Analysis by Dr Thibaut Benquey