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A2ML1 – Noonan Syndrome

Three unrelated individuals were reported with germline A2ML1 missense variants and clinical features of Noonan syndrome (Noonan syndrome). A de novo c.2405G>A (p.Arg802His) was identified in a case-parent trio, and two familial variants c.2405G>T (p.Arg802Leu) and c.1775G>T (p.Arg592Leu) were found on resequencing of 155 NS patients (PMID:24939586). Zebrafish expressing these A2ML1 variants exhibited broad head, blunted face and cardiac malformations, mirroring NS-like developmental defects (PMID:24939586).

Subsequent analysis of 15 individuals carrying rare A2ML1 variants showed all to be inherited from unaffected parents or explained by alternative genetic diagnoses, with no segregation support (PMID:33082526). Functional assessment pipelines further reported unclear significance for A2ML1 VUSs in RASopathy panels (PMID:29402968). Current evidence is conflicting and insufficient to establish a causal association between A2ML1 and Noonan syndrome. Key take-home: A2ML1 is not currently recommended for routine NS diagnostic panels.

References

  • European Journal of Human Genetics • 2015 • Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. PMID:24939586
  • European Journal of Human Genetics • 2021 • The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered. PMID:33082526
  • Scientific Reports • 2018 • Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies. PMID:29402968

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Three probands with de novo or familial A2ML1 missense variants and zebrafish functional data (PMID:24939586) but inheritance from unaffected parents in 15 individuals with no segregation (PMID:33082526).

Genetic Evidence

Limited

Three probands with A2ML1 variants in 3 families with no additional segregation (PMID:24939586) countered by 15 cases showing inherited variants without phenotype (PMID:33082526).

Functional Evidence

Moderate

Zebrafish models of p.Arg802His, p.Arg802Leu and p.Arg592Leu demonstrated NS-like craniofacial and cardiac defects, supported by structural modeling (PMID:24939586).