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Alstrom syndrome is a rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in the ALMS1 gene. Clinically, affected individuals present in infancy with cone-rod retinal dystrophy leading to blindness, sensorineural hearing impairment, childhood-onset obesity, insulin resistance progressing to type 2 diabetes, and dilated cardiomyopathy. Additional features may include global developmental delay, hepatic and renal dysfunction, and endocrine abnormalities such as hypogonadism (PMID:11941369). The syndrome’s broad phenotypic spectrum and age-dependent onset often lead to delayed diagnosis, underscoring the importance of molecular testing.
Genetically, ALMS1 variants cluster in exons 8, 10, and 16 but span the entire 23-exon coding region. Early linkage and transcript studies identified frameshift and nonsense mutations, including c.3781G>T (p.Glu1261Ter), segregating with disease in multiple unrelated families (PMID:11941369). Case reports and series have since described over 79 loss-of-function alleles in more than 500 affected individuals worldwide. Recurrent and founder mutations have been documented in English, Turkish, Saudi, and Chinese populations, with consanguinity unmasking homozygous alleles in large pedigrees.
Segregation analysis across at least six independent families demonstrates complete co-segregation of biallelic ALMS1 truncating variants with Alstrom syndrome phenotypes (PMID:11941370). Reports of compound heterozygous and homozygous variants in consanguineous kindreds confirm autosomal recessive inheritance. Founder alleles, such as c.10480C>T (p.Gln3494Ter) in Mennonite kindreds, illustrate population-specific variation and support genotype-phenotype correlations in early-onset cardiomyopathy.
Functional studies implicate ALMS1 in centrosome cohesion and primary cilium assembly. ALMS1 localizes to the proximal ends of centrioles and basal bodies, interacting with C-Nap1; knock-down in patient fibroblasts compromises centrosome cohesion and ciliary maintenance (PMID:20844083). Genotype-phenotype correlation studies reveal that exon-16 variants are associated with earlier retinal degeneration and cardiomyopathy, whereas exon-8 variants correlate with milder renal disease (PMID:17594715).
While the majority of evidence supports ALMS1 haploinsufficiency as the pathogenic mechanism, rare missense alleles altering splicing (c.9542G>A; p.Arg3181Gln) demonstrate variable expressivity and milder ocular phenotypes (PMID:36685911). Intrafamilial variability in cardiac outcomes underscores the influence of genetic modifiers and environmental factors. No robust refuting evidence has emerged, and disputes remain limited to variant-specific expressivity rather than the overall gene-disease link.
In summary, ALMS1 is definitively established as the causal gene for Alstrom syndrome, with autosomal recessive inheritance of predominantly truncating variants leading to a consistent multisystem phenotype. Clinical genetic testing of ALMS1 enables early diagnosis, informs surveillance for cardiomyopathy and endocrine complications, and guides family planning. Key take-home: Biallelic loss-of-function variants in ALMS1 should be sought in children presenting with early retinal dystrophy, obesity, hearing loss, and cardiomyopathy for precise diagnosis and management.
Gene–Disease AssociationDefinitiveBiallelic ALMS1 loss-of-function variants reported in >500 individuals across >79 alleles, segregation in six unrelated families, concordant functional studies Genetic EvidenceStrongMultiple consanguineous families with homozygous and compound heterozygous truncating ALMS1 variants in over 200 probands; reached genetic cap ([PMID:11941369]) Functional EvidenceModerateALMS1 localizes to centrosomes and basal bodies; knock-down impairs cilia assembly and centrosome cohesion in patient cells ([PMID:20844083]) |