LSM7 – Leukodystrophy

LSM7 has emerged as a strong candidate gene associated with leukodystrophy (MONDO_0019046), a neurodevelopmental disorder characterized by cerebellar atrophy (HP:0001272) and intellectual disability. Recent investigations have described patients with biallelic variants in LSM7, highlighting its clinical importance in pediatric neurodegenerative presentations (PMID:39420558). The clinical presentations include cerebellar atrophy on MRI, developmental delay, and features consistent with leukodystrophy.

A case report documented a patient carrying a homozygous variant, and another report described a compound heterozygous state. In both instances, the recurrent variant c.121G>A (p.Asp41Asn) was identified, establishing a noteworthy genotype–phenotype correlation (PMID:39420558). These findings support autosomal recessive inheritance with the contribution of multiple alleles impacting key amino acids crucial for the LSM complex function.

Multi‐patient studies have further strengthened the genetic association by reporting biallelic variants in unrelated individuals. One study identified two probands – one with a leukodystrophy diagnosis and another with prenatal lethality – both carrying pathogenic LSM7 variants, including c.206G>C (p.Arg69Pro) and the recurrent c.121G>A (p.Asp41Asn) (PMID:35047835). These series, in conjunction with the case reports, contribute to a robust dataset of at least three probands demonstrating consistent clinical findings.

Segregation analysis in these families, although not quantified by additional affected relatives in the reports, supports the autosomal recessive transmission of pathogenic variants. The recurrence of the c.121G>A (p.Asp41Asn) variant across independent studies provides further evidence, indicating a non-random, genotype-specific mechanism underlying the disease pathogenesis.

Genetic evidence is compelling with the identification of three probands harboring biallelic variants. Detailed molecular studies have shown that the recurrent variant c.121G>A (p.Asp41Asn) disrupts the structure and function of the LSM complex, a finding that is consistent across independent studies (PMID:39420558, PMID:35047835). This concordance between reported cases and variant recurrence solidifies the genetic evidence for the disease association.

Functional assessment studies provide strong support for the role of LSM7 in leukodystrophy. Experimental models, including affinity purification-mass spectrometry and zebrafish knockdown assays, have demonstrated that LSM7 variants lead to defective assembly of LSM complexes, resulting in neurodevelopmental deficits that mirror the human phenotype (PMID:35047835). Such consistent functional disruptions across studies corroborate the pathogenicity of the identified variants.

In conclusion, the integrative analysis of clinical, genetic, and functional evidence strongly supports the association between biallelic LSM7 variants and leukodystrophy with cerebellar atrophy. This robust evidence base not only assists diagnostic decision‑making but also enhances commercial and research applications by providing a clear molecular target for screening and potential therapeutic intervention.

Key Take‑home: Biallelic LSM7 variants, particularly the recurrent c.121G>A (p.Asp41Asn), represent a robust marker for leukodystrophy with cerebellar atrophy, underscoring the gene's clinical utility in diagnostic pipelines.

References

• HGG advances • 2024 • LSM7 variants involving key amino acids for LSM complex function cause a neurodevelopmental disorder with leukodystrophy and cerebellar atrophy PMID:39420558
• HGG advances • 2021 • Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease PMID:35047835

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