Identification of a novel compound heterozygous SMG9 variants in a Chinese family with heart and brain malformation syndrome using whole exome sequencing

SMG9-deficiency syndrome, also known as heart and brain malformation syndrome, is a very rare congenital genetic disorder mainly characterized by brain, heart, and growth and developmental abnormalities. This syndrome is an autosomal recessive disease resulting from mutations in the SMG9 gene, which encodes a critical component of nonsense-mediated mRNA decay. Thus far, only twelve SMG9 deficiency patients have been reported with five novel homozygous SMG9 mutations. The most frequent characteristic features of these patients are facial dysmorphism, severe global developmental delay, intellectual disability, congenital heart disease, growth restriction, microcephaly, and brain abnormalities. Herein, whole exome sequencing was performed to identify novel compound heterozygous SMG9 variants (NM_019108.3: c.1318_1319delAG (p.Ser440*) and c.947A>G (p.His316Arg)) in the proband, who exhibited syndromic intellectual disability. Mutations were confirmed as segregating in his affected sister and other unaffected family members by Sanger sequencing. The patients we describe here have a similar dysmorphology profile associated with SMG9-deficiency syndrome. Comparing the phenotype with that of patients in published reports, our patients can walk independently and their growth parameters are normal. In addition, short stature, failure to thrive, and microcephaly were not observed. Possible residual function of the H316R SMG9 variant could explain the milder phenotype observed in our patients. Our report is the first description of a non-consanguineous Chinese pedigree with novel compound heterozygous variants in the SMG9 gene. The molecular confirmation of the patient expands the genetic spectrum of SMG9-deficiency syndrome, and the manifestation of SMG9-deficiency syndrome in the patient provides additional clinical information regarding this syndrome.