Submissions for variant t(X;9)(q23;q12)dn

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics Division, Universidade Federal de Sao Paulo	RCV000727550	SCV000854429	likely pathogenic	Midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis	2016-03-01	no assertion criteria provided	research	We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally-inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is co-expressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alteration syndromes. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients’ features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient’s cells indicate a partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart and kidney alterations and elliptocytosis.