AMMECR1 – Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome

AMMECR1 is implicated in a clinically recognizable X-linked recessive condition, Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome (AMME syndrome). Affected males present with midface retrusion, proportionate short stature, elliptocytosis, variable anemia, sensorineural hearing loss, and in some cases nephrocalcinosis.

Inheritance is X-linked recessive with segregation demonstrated in two maternal half-brothers carrying a truncating AMMECR1 variant c.502C>T (p.Arg168Ter) ([PMID:28089922]). Additional evidence includes two unrelated male patients with microdeletions encompassing AMMECR1 identified by array-CGH ([PMID:30737907]). In total, four probands across three unrelated families support a robust gene-disease relationship.

The variant spectrum comprises truncating (c.502C>T (p.Arg168Ter)), frameshift (c.454dup (p.Arg152fs)), and missense (c.530G>A (p.Gly177Asp)) changes, as well as small Xq22.3q23 microdeletions. No recurrent founder variants have been reported, and allele frequencies are absent from population databases.

Functional assays in patient-derived and transfected cell lines reveal aberrant nuclear localization for p.Gly177Asp and p.Arg152fs mutants and predicted loss of function consistent with haploinsufficiency ([PMID:27811305]). Alternative splicing of exon 2 also suggests transcript instability in carriers of the p.Arg168Ter allele.

No conflicting reports have emerged to dispute the association of AMMECR1 with AMME syndrome, and contiguous deletions involving AMMECR1 consistently reproduce a core phenotype even when co-deleted with neighboring genes.

Integration of case-level and experimental data yields strong clinical validity: AMMECR1 loss-of-function variants reliably cause the AMME phenotype. Genetic testing of AMMECR1 informs diagnostic decision-making and genetic counseling for at-risk families.

References

• Gene • 2017 • X-linked elliptocytosis with impaired growth is related to mutated AMMECR1. PMID:28089922
• American Journal of Medical Genetics Part A • 2019 • Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis. PMID:30737907
• Journal of Medical Genetics • 2017 • AMMECR1: a single point mutation causes developmental delay, midface hypoplasia and elliptocytosis. PMID:27811305

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