CNNM4 – Jalili syndrome

CNNM4 (HGNC:105) is robustly associated with Jalili syndrome (MONDO_0009007), a rare autosomal recessive disorder characterized predominantly by cone-rod dystrophy and amelogenesis imperfecta, with occasional features of myopathy. This association is supported by multiple independent case reports and multi‐patient studies that have consistently identified biallelic pathogenic variants in CNNM4 in affected individuals (PMID:28586144).

Affected patients commonly present with progressive visual loss, dyschromatopsia, and photophobia alongside dental anomalies such as amelogenesis imperfecta. In some reports, additional manifestations including myopathic changes (e.g., muscle overgrowth) have been described, further broadening the phenotypic spectrum of the syndrome (PMID:28586144).

Multiple families have provided strong segregation evidence for an autosomal recessive inheritance pattern, with affected siblings consistently harboring homozygous or compound heterozygous mutations in CNNM4. At least 18 families have been documented where segregation analyses affirm the co‐inheritance of these variants with the disease phenotype (PMID:27070327).

The genetic evidence is further reinforced by the recurrent identification of diverse variant classes including missense, splice, and nonsense mutations. A representative example is the variant c.1076T>C (p.Leu359Pro) which has been identified in multiple affected individuals and successfully correlates with the clinical phenotype (PMID:28586144).

Functional studies have provided mechanistic insights by demonstrating that CNNM4 mutations lead to impaired magnesium transport and reduced protein stability. Experimental investigations, including protein expression assays and molecular dynamics simulations, consistently support a loss‐of‐function mechanism, thereby bolstering the causal role of these variants in Jalili syndrome (PMID:29322253, PMID:31347285).

Integrating the genetic and functional data, the evidence meets ClinGen criteria for a strong gene–disease association. The convergence of segregation data, recurrent mutation types, and corroborative functional assays underlines the clinical utility of identifying CNNM4 pathogenic variants in affected individuals, which in turn supports precise diagnostic decision‑making and informs potential therapeutic strategies.

Key Take‑home: The strong association between CNNM4 variants and the clinical features of Jalili syndrome makes genetic testing a valuable tool for diagnosis, risk assessment, and personalized management of affected patients.

References

• American journal of medical genetics. Part A • 2017 • Co-occurrence of Jalili syndrome and muscular overgrowth PMID:28586144
• Ophthalmic genetics • 2017 • A new familial case of Jalili syndrome caused by a novel mutation in CNNM4 PMID:27070327
• Molecular genetics and genomics : MGG • 2018 • Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1 PMID:29322253
• Molecular genetics & genomic medicine • 2019 • A novel pathogenic missense variant in CNNM4 underlying Jalili syndrome: Insights from molecular dynamics simulations PMID:31347285

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