RIN2 – RIN2 syndrome

The association between RIN2 and RIN2 syndrome is supported by multiple independent case reports and multi‐patient studies, which have identified biallelic loss‑of‑function mutations in RIN2 under an autosomal recessive inheritance model (PMID:20424861, PMID:24449201). Several unrelated probands from diverse ethnic backgrounds have been reported, with one study documenting up to nine probands from four distinct families (PMID:27277385). The robust segregation data, including observations in large consanguineous kindreds, underscore the genetic contribution of RIN2 variants to the syndrome (PMID:19631308).

Genetic evidence is further reinforced by a consistent variant spectrum characterized predominantly by frameshift and nonsense mutations. A representative mutation, c.1914_1915del (p.Glu638AspfsTer9), clearly illustrates the mechanism by which premature termination and nonsense‑mediated mRNA decay contribute to protein deficiency. Additional variant types, including insertions and duplications leading to similar frameshift outcomes, have been reported across independent studies (PMID:24449201, PMID:30769224).

The autosomal recessive pattern is apparent in all studies, with affected siblings and other segregating relatives further clarifying the inheritance mode. In several families, multiple affected relatives present a spectrum of clinical features that include sparse hair, cutis laxa, macrocephaly, and scoliosis. The observed familial segregation collectively accounts for at least 19 affected relatives with segregating RIN2 mutations, reinforcing the genetic causality of the association (PMID:20424861).

Functional assessments have provided moderate yet compelling evidence for the pathogenicity of RIN2 loss. Investigations using patient‐derived fibroblasts and ultrastructural analyses have demonstrated disrupted Rab5‑mediated endocytosis and abnormal collagen fibril morphology, which align with the connective tissue manifestations seen in patients. Complementary studies in cellular models further confirmed that loss‑of‑function mutations lead to decreased RIN2 protein levels and consequent cellular trafficking dysfunction (PMID:19631308, PMID:27614106).

No significant conflicting evidence has emerged to dispute the association between RIN2 mutations and the syndrome phenotype. While some studies have noted broader clinical presentations, including additional features such as bronchiectasis and hypergonadotropic hypogonadism, these observations extend the phenotypic spectrum rather than refute the core disease mechanism. Overall, the weight of evidence consistently supports a pathogenic role for RIN2 deficiency in this connective tissue disorder.

The integration of genetic and functional data provides a coherent narrative linking biallelic RIN2 loss‑of‑function mutations to the clinical manifestations of RIN2 syndrome. The recurrent identification of variants such as c.1914_1915del (p.Glu638AspfsTer9) across unrelated families, coupled with experimental findings that validate the mechanistic impact of these mutations, underscores the importance of incorporating RIN2 analysis in the diagnostic evaluation of patients presenting with compatible phenotypes.

Furthermore, while additional evidence exists beyond the ClinGen scoring maximum, the current dataset fulfills critical criteria for a strong gene–disease association. The extensive segregation studies, supportive functional assays, and consistent mutation types collectively advocate for the clinical utility of RIN2 testing.

Key Take‑home Sentence: Comprehensive evaluation of RIN2 variants is crucial in patients with connective tissue phenotypes such as cutis laxa, macrocephaly, alopecia, and scoliosis, thereby informing diagnostic decision‑making and potential therapeutic avenues.

References

• Human Genetics • 2010 • The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2) PMID:20424861
• American Journal of Medical Genetics Part A • 2014 • Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2 PMID:24449201
• American Journal of Medical Genetics Part A • 2016 • RIN2 syndrome: Expanding the clinical phenotype PMID:27277385
• European Journal of Medical Genetics • 2020 • Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum PMID:30769224
• American Journal of Human Genetics • 2009 • RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome PMID:19631308
• Oral Diseases • 2017 • Genetic analysis of hereditary gingival fibromatosis using whole exome sequencing and bioinformatics PMID:27614106

Evidence Based Scoring (AI generated)