Congenital Heart Defect

Gene: SMG9

Green List (high evidence)

Multiple unrelated families reported.

Created: 22 Nov 2023, 5:06 a.m. | Last Modified: 22 Nov 2023, 5:06 a.m.

Panel Version: 0.363

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Heart and brain malformation syndrome, MIM# 616920

Red List (low evidence)

Autosomal recessive inheritance

Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts.

The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10).

In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene.

In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes.

In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.
Sources: Literature

Created: 17 Nov 2023, 8:33 a.m. | Last Modified: 17 Nov 2023, 8:34 a.m.

Panel Version: 0.315

Mode of inheritance
Other

Phenotypes
Heart and brain malformation syndrome (HBMS)

Publications

• 27018474 31390136 32412169 33609422