A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset

Abstract

Background: JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC).

Case report: Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene.

Conclusion: Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

Keywords: JAM3; Seizures; Cerebral hemorrhages; Cataracts; Neonate; Infant; COL4A1.

Fig. 1

Axial T2-weighted (A) and susceptibility weighted imaging (B) of brain MRI showed severe intraventricular hemorrhage and bilateral multiple intraparenchymal hemorrhages, prevailing in the left hemisphere, and enlargement of the posterior horns of the lateral ventricles. Coronal T2-weighted (C) showed multiple cysts in the frontal periventricular white matter. Sagittal T1-weighted (D) revealed also a large intraventricular clot in the III ventricle and hypoplasia of cerebellar vermis. Multiple periventricular calcifications (arrows) were demonstrated on phase axial susceptibility weighted image (E), on T1-weighted (F) image, and on corresponding axial CT (G). There was no evidence of venous thrombosis and vascular malformation on MR venogram (H) and time of flight angiography (not shown)

Fig. 2

(A) Sanger sequencing confirmed the homozygous variation, c.690 T > G, in the proband. (B and C) Sanger sequencing shown that the parents were both carrying the heterozygous variation

Fig. 3

The patient during NICU stay (A–B), at 12 months (C) and at 24 months (D)

Fig. 4

Axial (A–E) and coronal (F-L) T2-weighted images of serial brain MRI: (A,F) 1 month of life, (B–G) 3 months of life, (C–H) 4 months of life, (D–I) 15 months of life, (E–L) 2 years of life. Serial MRI scans showed porencephalic cystic evolution and reduced white-matter volume (indicative of destructive changes), and consensual gradual worsening of ventricular dilatation unless a ventriculoperitoneal shunt was implanted at 4 months of life. Last two MRI exams (D-I and E-L) showed a plastic re-organization of porencephalic cysts and lateral ventricles with reduction of signs of cerebrospinal fluid’s decompensation