The gene at the center of the case is COL4A1, located on chromosome 13, which encodes the alpha-1 chain of Type IV collagen. Together with the alpha-2 chain produced by COL4A2, it forms the core scaffold of vascular basement membranes — the molecular meshwork that gives small blood vessels their structural integrity. When COL4A1 is disrupted, the smallest vessels of the brain, kidney, and eye become inherently fragile. Researchers first established in earlier work that COL4A1 missense mutations cause an autosomal dominant cerebral small vessel disease with hemorrhagic stroke, and the resulting condition is now known as Gould syndrome. Its spectrum stretches from fetal intracranial hemorrhage and porencephaly in the womb to adult-onset lacunar infarction and cognitive decline decades later.

What makes Gould syndrome so elusive is its marked incomplete penetrance and variable expressivity. De novo mutations account for roughly 40 percent of cases, but many carriers remain asymptomatic for years, with isolated microscopic hematuria or subtle ocular findings as the only clues. Affected women of reproductive age frequently escape diagnosis until a severe fetal phenotype forces clinicians to look backward at the parent — a strategy known as reverse phenotyping. The stakes are considerable: approximately 28 percent of severe fetal brain lesions harbor pathogenic variants in COL4A1 or COL4A2, and more than 60 percent of carriers of such variants develop ventriculomegaly or fetal growth restriction in the second or third trimester. Prenatal MRI can detect the resulting porencephaly, schizencephaly, and other structural anomalies early.

In the second pregnancy of this case, fetal MRI at 22 weeks and 4 days demonstrated Grade IV hemorrhage in the left periventricular germinal matrix with mild left ventriculomegaly, the ventricular width measuring 10.87 millimeters. Follow-up imaging at 27 weeks and 4 days showed partial resolution of the hematoma — but progression to severe ventriculomegaly at 21.36 millimeters, graded on the Society for Maternal-Fetal Medicine scale. Amniotic fluid karyotyping, copy-number sequencing, and cytomegalovirus testing had all been normal. In the third pregnancy, ultrasound at 23 weeks and 3 days revealed a mixed-echogenicity mass in the region of the left choroid plexus, with internal and peripheral vascularity on color Doppler. Fetal MRI the next day confirmed the same Grade IV periventricular hemorrhage, this time with extension into the basal ganglia and mild ventriculomegaly at 10.47 millimeters. By 28 weeks, the hematoma had partially resolved but the left ventricle had progressed to severe dilatation at 15.96 millimeters.

The third pregnancy brought a second ominous thread: fetal growth restriction. The estimated fetal weight fell from 522 grams at the 18th percentile at 23 weeks and 3 days to 857 grams at the 0.2nd percentile at 28 weeks and 3 days, with abdominal circumference, head circumference, and femur length all below the 3rd percentile on the NICHD fetal growth reference. Because fetal intracranial hemorrhage can also stem from thrombocytopenia, coagulation disorders, or congenital infection, the team systematically excluded alternatives: maternal platelet counts, coagulation profiles, and TORCH screening were unremarkable. Fetal blood sampling was not performed, so fetal-specific hematological causes could not be definitively excluded — but none of those diagnoses was supported by the available investigations. The anatomically concordant recurrence across two pregnancies pointed instead toward an inherited vascular predisposition.

That suspicion triggered the pivotal move of the case: systematic reverse phenotyping of the mother. History-taking and physical examination disclosed previously unrecognized multi-system abnormalities. She had suffered left lower-limb claudication since childhood, long misattributed to poliomyelitis sequelae. Examination revealed left clubfoot deformity, bilateral leg-length and girth asymmetry, left upper-limb weakness graded 4 out of 5, and left-sided hypoesthesia. Maternal cranial MRI, performed at around 24 weeks of gestation, showed continuous unilateral volume loss running from the right posterior limb of the internal capsule through the cerebral peduncle, pons, and medulla — chronic Wallerian degeneration of the right corticospinal tract, with compensatory dilatation of the right lateral ventricle to 15.8 millimeters. Her renal work-up found persistent microscopic hematuria without proteinuria and a 1.2-centimeter simple cyst in the right kidney. Funduscopy documented retinal arteriolar tortuosity and arteriovenous nicking — findings recorded before the onset of preeclampsia, which developed at 27 weeks with blood pressure of 150/85 mmHg and proteinuria.

The genetic strategy was equally instructive. Previous karyotyping and copy-number sequencing had been normal, so the team performed trio whole-exome sequencing on the mother, father, and fetal amniocytes on an Illumina NovaSeq 6000 platform, with target coverage of at least 99 percent and mean depth of at least 100-fold. Sequencing identified a heterozygous missense variant, COL4A1 c.4249G>C, resulting in the substitution p.Gly1417Arg, in the fetus and the mother; the father was wild-type, and Sanger sequencing confirmed co-segregation. The variant sits in exon 48 and disrupts a highly conserved glycine within the Gly-X-Y motif of the collagen triple helix — a structural domain where glycine residues are essential to helix assembly. Computational predictors supported a deleterious effect, with REVEL scoring 0.977, SIFT 0.00, and PolyPhen-2 1.000, and the allele frequency is zero in the gnomAD v4.0 East Asian population. Yet under strict ACMG/AMP criteria — applying PM1 for the critical functional domain, PM2_Supporting for absence from population databases, and PP3 for computational evidence — the variant was classified as a variant of uncertain significance. De novo status could not be assessed without grandparental samples, and the variant is absent from ClinVar and HGMD.

Integrated copy-number analysis run in parallel with the exome data revealed a second maternal finding: an approximately 1.33-megabase heterozygous deletion at 17p12, encompassing the entire PMP22 gene and independently validated by low-pass copy-number sequencing. The region carries a ClinGen haploinsufficiency score of 3 and is associated with hereditary neuropathy with liability to pressure palsies. Crucially, fetal copy-number sequencing confirmed that the fetus did not inherit the deletion — so it could not explain the fetal hemorrhage. Its value lay in refining the maternal phenotype and informing reproductive counseling rather than resolving the prenatal presentation, and it does not account for the mother’s central motor deficit, which is anatomically explained by corticospinal tract degeneration. Each variant segregates independently, yielding a 50 percent per-pregnancy inheritance probability for each and a 25 percent probability of co-inheritance — probabilities the authors stress must never be equated with disease-risk estimates, given the uncertain significance of the COL4A1 variant and the incomplete penetrance of COL4A1-associated disorders.

The clinical integration that followed offers a template for managing a prenatal variant of uncertain significance. A multidisciplinary review spanning prenatal diagnosis, neonatology, ultrasound, and radiology considered fetal and maternal indications separately. For the fetus, Grade IV periventricular hemorrhage with progressive severe ventriculomegaly and early-onset growth restriction carried a high risk of severe neurodevelopmental impairment irrespective of the genetic findings; the COL4A1 variant, as a VUS, was not itself used as an indication. For the mother, early-onset preeclampsia together with the cerebral and retinal small-vessel changes raised concern that continued gestation could add to her vascular burden — but because of the VUS classification, any contribution of the variant to maternal cerebrovascular risk was communicated as uncertain, never as an established risk. With no curative intrauterine intervention available, the couple elected termination at 29 weeks after informed consent. The mother’s post-termination course was uneventful, with resolution of hypertension and proteinuria.

The authors are transparent about the limits of their conclusions. Fetal autopsy was declined, precluding ultrastructural verification of basement-membrane abnormalities. The fetus of the second pregnancy was tested only by karyotyping and copy-number sequencing, never for the COL4A1 variant, so attribution of both hemorrhages to the same variant remains presumptive — although the imaging patterns were strikingly similar. Functional validation of the variant is ongoing through a collaborative cell-model project, and EMG and nerve conduction studies were not performed to quantify peripheral nerve involvement from the 17p12 deletion. Umbilical artery Doppler data were unavailable, so fetal growth restriction was defined biometrically. For future pregnancies, the family’s options include chorionic villus sampling or amniocentesis with COL4A1 testing and copy-number sequencing, while preimplantation genetic testing could establish whether an embryo inherits the variant without establishing its pathogenicity. The broader lesson stands on firmer ground: recurrent, anatomically concordant fetal intracranial hemorrhage should prompt clinicians to look not only at the fetus, but at the mother — whose own brain, kidneys, and retinas may have been carrying the diagnosis all along.

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

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

Article References: Shi, W., Xu, H., Pu, C., Liang, Y., Zhao, T., Wang, X., Liu, Z., Zhang, C., Li, T., & He, F. (2026). Prenatal Diagnosis of Recurrent Fetal Intracranial Hemorrhage and a Maternally Inherited COL4A1 Variant of Uncertain Significance: A Case Report With Maternal Reverse Phenotyping. Clinical Case Reports, 14(11), Article e73525. https://doi.org/10.1002/ccr3.73525

Image Credits: AI Generated

DOI: 10.1002/ccr3.73525

Keywords: Prenatal, Diagnosis, Recurrent, Fetal, Intracranial, Hemorrhage, Maternally, Inherited, COL4A1, Variant, Uncertain, Significance