Heart And Brain Malformation Syndrome

A number sign (#) is used with this entry because of evidence that heart and brain malformation syndrome (HBMS) is caused by homozygous mutation in the SMG9 gene (613176) on chromosome 19q13.

Description

Heart and brain malformation syndrome is a severe autosomal recessive multiple congenital anomaly syndrome characterized by profoundly delayed psychomotor development, dysmorphic facial features, microphthalmia, cardiac malformations, mainly septal defects, and brain malformations, including Dandy-Walker malformation (summary by Shaheen et al., 2016).

Clinical Features

Shaheen et al. (2016) reported 2 unrelated consanguineous families of Arab origin in which 5 patients had a severe multiple congenital anomaly syndrome. In the first family, the proband was a female infant who died at age 7 weeks. Antenatal ultrasound showed polyhydramnios, splaying of the cerebellum, and a ventricular septal defect. At birth, she showed craniofacial abnormalities, including prominent forehead and occiput, wide anterior fontanel, low-set malformed ears, depressed nasal bridge with anteverted nares, microphthalmia, and high-arched palate. She also had clenched hands with camptodactyly. Brain imaging showed Dandy-Walker malformation, cerebellar vermis hypoplasia, and hypoplastic corpus callosum. Cardiac abnormalities included interrupted aortic arch, hypoplastic valves, and ventricular septal defect. She developed seizures and sepsis, resulting in death. Family history revealed that the mother had a history of 3 abortions, and there were 2 older sibs with multiple congenital anomalies who died in utero or in the first year of life. In a second family, 2 children, aged 2 and 3 years, had poor overall growth, dysmorphic features, microcephaly (up to -6 SD), profoundly delayed psychomotor development with hypotonia and hyperreflexia, poor vision, and cardiac ventricular septal defects. Brain imaging in both patients showed brain atrophy; 1 patient had Dandy-Walker malformation and decreased myelination, whereas the other had a thin corpus callosum. Dysmorphic features were detailed in 1 patient, who showed narrow forehead, prominent metopic suture, widow's peak, hypertelorism, posteriorly rotated ears, broad nasal bridge, full and everted lower lip, cleft lip, and small eyes. Laboratory studies were unremarkable.

Inheritance

The transmission pattern of HBMS in the families reported by Shaheen et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated consanguineous Arab families with HBMS, Shaheen et al. (2016) identified 2 different homozygous truncating mutations in the SMG9 gene (613176.0001 and 613176.0002). The mutations, which were found by a combination of homozygosity mapping, linkage analysis, and exome sequencing, segregated with the disorder in the families. Studies of 1 patient's cells showed complex absence of the SMG9 protein, and the truncated isoform could not be detected, indicating that nonsense-mediated mRNA decay had occurred. Analysis of patient cells showed dysregulation of the transcriptional profile compared to controls, although there was not widespread impairment of nonsense-mediated mRNA decay.

Animal Model

Shaheen et al. (2016) found that homozygosity for a truncating mutation in the Smg9 gene was embryonic lethal in mice. Examination of homozygous null murine embryos showed a range of abnormalities, including edema, hemorrhage, exencephaly, preaxial polydactyly, decreased size of the mid- and hindbrains, microphthalmia, thin myocardium, and cardiac septal defects. These phenotypes were variable among mutant embryos; there was evidence of incomplete penetrance, but most embryos showed clear phenotypic abnormalities. The findings supported a role for Smg9 in brain, heart, and eye development.