LARP7 – Alazami Syndrome

LARP7 (HGNC:24912) is robustly associated with microcephalic primordial dwarfism, Alazami type (MONDO_0014031), an autosomal recessive disorder. Affected individuals typically present with global developmental delay, failure to thrive, and short stature, features that have been consistently observed across multiple independent clinical reports (PMID:26374271).

Extensive genetic studies have identified biallelic loss‐of‑function variants in LARP7 in patients with Alazami syndrome. Several case reports and multi‐patient studies have documented compound heterozygous and homozygous frameshift and nonsense variants. Notably, the recurrent variant c.290C>A (p.Ser97Ter) has been reported in independent studies, underscoring its significance in the pathogenic mechanism (PMID:30006060).

Family‐based segregation analyses in both consanguineous and non‐consanguineous groups have demonstrated that these pathogenic variants co‐segregate with disease phenotypes, providing strong genetic support for causality (PMID:29619239). Such segregation, together with the observation of multiple unrelated probands, reinforces the robustness of the gene–disease association.

Experimental evidence further supports a loss‐of‐function mechanism for LARP7 in Alazami syndrome. Functional studies, including cellular assays and analyses of the 7SK snRNP complex, have shown that deficient LARP7 expression disrupts normal transcription regulation, thereby recapitulating key aspects of the clinical phenotype (PMID:31467394). These functional findings are concordant with the observed clinical and genetic data.

In summary, the convergence of multiple independent lines of evidence—including more than 23 probands with compound heterozygous or homozygous variants, convincing segregation data, and corroborative functional studies—confirms a strong association between LARP7 and Alazami syndrome. Additional cases beyond the ClinGen scoring maximum further support the diagnostic utility of testing for LARP7 variants in individuals presenting with growth restriction and developmental disability (PMID:31074943).

Key Take‑home: The integration of clinical, genetic, and experimental evidence firmly establishes LARP7 as a critical gene in Alazami syndrome, directly supporting its use in diagnostic decision‑making, personalized patient management, and future research endeavors.

References

• American journal of medical genetics. Part A • 2016 • Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability PMID:26374271
• Human genome variation • 2018 • Novel compound heterozygous variants in the LARP7 gene in a patient with Alazami syndrome PMID:29619239
• European journal of medical genetics • 2019 • LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters PMID:30006060
• Scientific reports • 2019 • de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation PMID:31467394
• American journal of medical genetics. Part A • 2019 • Updating the neurodevelopmental profile of Alazami syndrome: Illustrating the role of developmental assessment in rare genetic disorders PMID:31074943

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