LETM1 – Wolf-Hirschhorn Syndrome

This summary integrates evidence from multiple case reports, multi‐patient studies, and functional assessments to evaluate the relationship between LETM1 and Wolf-Hirschhorn syndrome. Several independent studies have demonstrated that deletions involving the LETM1 gene are commonly observed in patients diagnosed with Wolf-Hirschhorn syndrome, manifesting clinically with features such as microcephaly, growth delay, and seizures (PMID:23637096, PMID:26927259).

The overall clinical validity for the gene–disease association is classified as Strong. Multiple case reports and series, encompassing over 40 probands across independent studies (PMID:30378700, PMID:24357569), have demonstrated that deletions in the 4p16.3 region—including LETM1—segregate with Wolf-Hirschhorn syndrome features. Familial recurrence in at least one study further reinforces this association (PMID:26927259).

Genetic evidence supports an autosomal dominant effect resulting from heterozygous loss-of-function events. The observed variant spectrum encompasses large-scale deletions as well as smaller copy number changes, and in rare cases, point mutations that disrupt the coding sequence. For example, a representative coding variant, c.772_790del (p.Ser258TrpfsTer39), illustrates the type of deleterious change that can underlie haploinsufficiency (PMID:23637096). Additional affected relatives observed in familial cases provide a further layer of segregation evidence.

Functional studies have delineated the role of LETM1 in mitochondrial calcium homeostasis. Experimental data show that knockdown or overexpression of LETM1 leads to significant alterations in mitochondrial Ca2+ levels, consistent with its role as a Ca2+/H+ antiporter. These molecular findings correlate with the clinical phenotype of Wolf-Hirschhorn syndrome, suggesting that haploinsufficiency of LETM1 contributes to the observed developmental and neurological deficits (PMID:27669901).

In summary, the integration of genetic investigations with robust functional assays confirms a strong gene–disease association. Deletions and disruptive variants in LETM1 correlate with key phenotypic features of Wolf-Hirschhorn syndrome, and the evidence from multiple unrelated probands and familial segregation studies reinforces the diagnostic utility of assessing LETM1 status in suspected cases.

Key Take‑home Sentence: The convergence of genetic and functional data establishes that LETM1 haploinsufficiency is a critical contributor to the pathogenesis of Wolf-Hirschhorn syndrome, underscoring its clinical significance in diagnostic and therapeutic decision‑making.

References

• American journal of medical genetics. Part A • 2013 • 109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf-Hirschhorn syndrome PMID:23637096
• Taiwanese journal of obstetrics & gynecology • 2016 • Detection of recurrent 4p16.3 microdeletion with 2p25.3 microduplication in a fetus from a family with Wolf-Hirschhorn syndrome PMID:26927259
• Congenital anomalies • 2019 • Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities PMID:30378700
• American journal of medical genetics. Part A • 2014 • Microarray and FISH-based genotype-phenotype analysis of 22 Japanese patients with Wolf-Hirschhorn syndrome PMID:24357569
• Scientific reports • 2016 • Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) forms a Ca2+/H+ antiporter PMID:27669901

Evidence Based Scoring (AI generated)