Key result
Whole exome sequencing of an SMA discordant family identified compound heterozygous mutations in TLL2 in the mildly affected male patient, which are predicted to be pathogenic and likely alleviate disease severity.
Why the study?
The severity of many spinal muscular atrophy cases, especially within a family, fails to be explained by known modifiers, leaving other modifiers unexplored.
Case Report (n=4)
The identification of a novel mutation in TLL2, an activator of myostatin, may explain the milder phenotype in a male SMA patient and broadens the spectrum of genetic modifiers for SMA.
BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder threating hundreds of thousands of lives worldwide. And the severity of SMA differs among different clinical types, which has been demonstrated to be modified by factors like SMN2, SERF1, NAIP, GTF2H2 and PLS3. However, the severities of many SMA cases, especially the cases within a family, often failed to be explained by these modifiers. Therefore, other modifiers are still waiting to be explored. CASE PRESENTATION: In this study, we presented a rare case of SMA discordant family with a mild SMA male patient and a severe SMA female patient. The two SMA cases fulfilled the diagnostic criteria defined by the International SMA Consortium. With whole exome sequencing, we confirmed the heterozygous deletion of exon7 at SMN1 on the parents' genomes and the homozygous deletions on the two patients' genomes. The MLPA results confirmed the deletions and indicated that all the family members carry two copies of SMN2, SERF1, NAIP and GTF2H2. Further genomic analysis identified compound heterozygous mutations at TLL2 on the male patient's genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient's genome. TLL2 is an activator of myostatin, which negatively regulates the growth of skeletal muscle tissue. Mutation in TLL2 has been proved to increase muscular function in mice model. VPS13A encodes proteins that control the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. And AGAP5 was reported to have GTPase activator activity. CONCLUSIONS: We reported a case of SMA discordant family and identified mutations at TLL2, VPS13A and AGAP5 on the patients' genomes. The mutations at TLL2 were predicted to be pathogenic and are likely to alleviate the severity of the male SMA patient. Our finding broadens the spectrum of genetic modifiers of SMA and will contribute to accurate counseling of SMA affected patients and families.
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Jiang et al. (2019) conducted a case report in Spinal muscular atrophy (n=4). TLL2, VPS13A, and AGAP5 mutations vs. Unaffected family members / wild-type alleles was evaluated on Identification of pathogenic genetic variants. Whole exome sequencing of an SMA discordant family identified compound heterozygous mutations in TLL2 in the mildly affected male patient, which are predicted to be pathogenic and likely alleviate disease severity.
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