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TLL2 – Spinal Muscular Atrophy

In a recent report, compound heterozygous mutations in TLL2 were identified in a spinal muscular atrophy (SMA) discordant family, highlighting a possible modifier role for this gene. The affected male patient carried two variants that segregated with a milder SMA phenotype, consistent with an autosomal recessive inheritance pattern (PMID:31888525). Genetic evidence is limited to this single family, where one affected proband harbored the mutation c.1609C>T (p.His537Tyr), with the second reported alteration, c.112G>C (p.Glu38Gln), also observed but not selected here for brevity. Functional studies further support TLL2’s role by demonstrating that alteration of its activity enhances muscular function in murine models, thereby concordantly linking experimental data with the clinical phenotype (PMID:31888525). Despite the promising functional assessment, the evidence remains insufficient for a robust gene-disease association due to the limited number of affected individuals and absence of extensive segregation data. Overall, the integration of genetic findings and functional experimental data suggests that TLL2 may serve as a genetic modifier in SMA, warranting further validation in larger cohorts.

References

  • BMC medical genetics • 2019 • Genomic analysis of a spinal muscular atrophy discordant family identifies a novel mutation in TLL2, an activator of growth differentiation factor 8 (myostatin): a case report PMID:31888525

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Evidence is derived from a single SMA discordant family with compound heterozygous mutations in TLL2 in one affected proband (PMID:31888525); limited segregation data restricts broader confidence.

Genetic Evidence

Limited

Two compound heterozygous variants, including c.1609C>T (p.His537Tyr), were observed in the male patient consistent with a recessive pattern; however, the observations are confined to one family (PMID:31888525).

Functional Evidence

Moderate

Functional assays demonstrate that TLL2, an activator of myostatin, enhances muscular performance in mouse models, thus providing supportive experimental evidence aligned with the clinical presentation (PMID:31888525).