Bi-allelic variants in WDHD1 cause microcephalic primordial dwarfism.

Deficiency of replisome scaffolding protein WDHD1/AND-1/Ctf4 — impaired replication fork stability and sister chromatid cohesion defect

WDHD1, encoding the replisome scaffolding protein AND-1/Ctf4, is identified as a novel microcephalic primordial dwarfism (MPD) gene through bi-allelic hypomorphic variants in 17 subjects from 14 independent families. Beyond classic MPD, the phenotypic spectrum includes severe congenital heart defects, hematological abnormalities, and Leigh syndrome-like neurological involvement. Patient fibroblasts exhibit globally reduced replication fork speed, spontaneous DNA damage, G1-to-S transition defects, and abnormal nuclear morphology including micronuclei, multilobed nuclei, and premature sister chromatid separation.

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With 17 subjects from 14 families, WDHD1 joins the growing list of replisome-related MPD genes with strong evidence at first report. The phenotypic extension to acute liver failure is a critical clinical signal: WDHD1 analysis should be prioritized in any MPD case with unexplained liver disease. This discovery further expands the genetically heterogeneous group of replication-associated primordial dwarfisms.

Clinical impact : 2/3 · Evidence strength : 3/3 · Novelty : 2/2 · Sample size : 1/1 · Journal quality : 1/1 → Total : 9/10