Prenatal Diagnosis of Recurrent Fetal Intracranial Hemorrhage and a Maternally Inherited COL4A1 Variant of Uncertain Significance: A Case Report With Maternal Reverse Phenotyping

A 33‐year‐old woman with two consecutive pregnancies affected by fetal left periventricular germinal matrix hemorrhage (Grade IV) and progressive ventriculomegaly underwent trio whole‐exome sequencing. A heterozygous COL4A1 c.4249G>C (p.Gly1417Arg) variant, classified as a variant of uncertain significance, was identified in the fetus of the current pregnancy and found to be maternally inherited; concurrent copy‐number analysis incidentally detected a maternal 17p12 microdeletion encompassing PMP22, which was not inherited by the fetus. Systematic reverse phenotyping of the mother revealed right corticospinal tract Wallerian degeneration, persistent microscopic hematuria, a renal cyst, and retinal arteriolar changes—a phenotype compatible with the COL4A1‐associated spectrum, although molecular causality remains unproven. Following multidisciplinary review, the pregnancy was terminated at 29 weeks, primarily on the basis of the grave fetal prognosis, with early‐onset preeclampsia contributing to the overall maternal risk assessment; the mother's post‐termination course was uneventful, with resolution of hypertension and proteinuria. This case illustrates that recurrent anatomically congruent fetal intracranial hemorrhages may prompt maternal reverse phenotyping that identifies maternally inherited COL4A1 variants of uncertain significance, and underscores the need to distinguish phenotypic concordance from proven molecular causality in prenatal counseling.