SKIV2L – Trichohepatoenteric Syndrome

Trichohepatoenteric syndrome (THES; MONDO:0009105) is a rare autosomal recessive disorder caused by biallelic variants in the RNA helicase gene SKIV2L. Affected individuals present in the neonatal period with intrauterine growth retardation, intractable diarrhea, woolly hair, facial dysmorphism, immunodeficiency and liver involvement.

Genetic studies have identified over 200 patients from unrelated families harboring pathogenic SKIV2L variants, including missense, nonsense, frameshift and splice‐site changes across all 28 exons (PMID:22444670; PMID:29527791; PMID:34414925). Notable variants include c.1891G>A (p.Gly631Ser) and c.1120C>T (p.Arg374Ter), each reported in multiple ethnic backgrounds and confirmed by Sanger sequencing (PMID:27431780; PMID:29484573).

Segregation analysis in consanguineous and non‐consanguineous families has confirmed recessive inheritance with compound heterozygosity or homozygosity in at least six affected sibships, supporting pathogenicity of loss‐of‐function alleles (PMID:29145277; PMID:30397475).

Functional assays demonstrate reduced SKIV2L protein expression in patient PBMCs by flow cytometry and western blot (PMID:29145277), deleterious effects on protein stability predicted by structural modeling (PMID:29484573), and a B cell–specific Skiv2l knockout mouse that recapitulates the human immunodeficiency phenotype, showing pro‐B cell arrest, DNA damage and defective V(D)J recombination (PMID:35658009).

No conflicting reports have been published to date disputing the role of SKIV2L in THES. The collective data support a loss‐of‐function mechanism in which removal of SKIV2L from the SKI RNA‐exosome complex causes multi‐system disease.

Key take-home: Biallelic SKIV2L variants are a definitive cause of autosomal recessive THES; molecular testing should include full coding and splice junction analysis to guide early diagnosis and nutritional and immunological management.

References

• American Journal of Human Genetics • 2012 • SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome PMID:22444670
• Human Mutation • 2018 • Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects PMID:29527791
• Saudi Journal of Gastroenterology • 2022 • Tricho-hepato-enteric syndrome: Retrospective multicenter experience in Saudi Arabia PMID:34414925
• Molecular Medicine Reports • 2016 • Targeted next-generation sequencing identification of a novel missense mutation of the SKIV2L gene in a patient with trichohepatoenteric syndrome PMID:27431780
• Medicine • 2017 • Tricho-hepato-enteric syndrome with novel SKIV2L gene mutations: A case report PMID:29145277
• SAGE Open Medical Case Reports • 2018 • Trichohepatoenteric syndrome: A rare mutation in SKIV2L gene in the first Balkan reported case PMID:30397475
• Digestive Diseases and Sciences • 2018 • Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome PMID:29484573
• Science Immunology • 2022 • The mammalian SKIV2L RNA exosome is essential for early B cell development PMID:35658009

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