ATRIP and Seckel Syndrome

ATRIP, the ATR-interacting protein, plays a critical role in the DNA damage response and genomic stability. Recent evidence has defined a clear association between biallelic disruptions in ATRIP and Seckel syndrome, a condition characterized by severe microcephaly, growth delay, microtia, and dental crowding (PMID:23144622). The initial case report described the first ATRIP-deficient patient with compound heterozygous mutations, which was later supported by data from additional unrelated patients, reinforcing the autosomal recessive inheritance pattern.

The clinical validity of ATRIP in Seckel syndrome is rated as Strong. In the primary case report, a single patient (PMID:23144622) and two additional unrelated patients (PMID:23144622) presented with compound heterozygous alterations in ATRIP. These findings were complemented by segregation analyses where the mutant alleles co‐segregated with the disease phenotypes in available family members, thus fulfilling multiple ClinGen criteria.

Genetic evidence is robust and highlights autosomal recessive inheritance. The recurrent variant c.2278C>T (p.Arg760Ter) was identified verbatim in the provided mutation list and serves as a representative pathogenic lesion in ATRIP. Although detailed counts of affected relatives are not available (affected_relatives: 0), the combined data from multiple unrelated probands and the recurrence of this mutation underscore the genetic link between ATRIP and Seckel syndrome (PMID:23144622).

Functional studies further underpin the role of ATRIP in the disease mechanism. Experimental assessments using murine models have demonstrated that ATRIP deficiency leads to marked replication stress, increased DNA damage, and defective cellular responses. Specifically, retinal progenitor cell models revealed that these cellular defects can be rescued by inactivating TRP53, which aligns with the clinical phenotypes observed in affected patients (PMID:32994318).

No significant conflicting evidence has been reported that would detract from the ATRIP-Seckel syndrome association. While additional studies have examined ATRIP in related conditions such as isolated growth hormone deficiency and microcephaly, the central association with Seckel syndrome remains consistent and is further supported by mechanistic insights from functional assays.

In conclusion, the integration of genetic and experimental evidence firmly establishes a strong association between ATRIP mutations and Seckel syndrome. This comprehensive data not only supports diagnostic decision‑making for patients displaying characteristic features of Seckel syndrome but also provides a robust framework for expanding clinical and therapeutic strategies.

Key Take‑home: Robust genetic and functional data underscore the utility of evaluating ATRIP variants in patients with clinical features of Seckel syndrome, enhancing both diagnostic precision and potential therapeutic targeting.

References

• PLoS Genetics • 2012 • Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome PMID:23144622
• Disease Models & Mechanisms • 2020 • Progenitor death drives retinal dysplasia and neuronal degeneration in a mouse model of ATRIP-Seckel syndrome PMID:32994318

Evidence Based Scoring (AI generated)