Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis

Abstract

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.

Case Report: Contiguous Xq22.3 Deletion Associated with ATS-ID Syndrome: From Genotype to Further Delineation of the Phenotype

“…In case of ATS-ID, exome sequencing analyses provided data connecting missense and nonsense pathogenic variants in AMMECR1 with occurrence of elliptocytosis, cardiac and bone defects, ID, and midface hypoplasia (Andreoletti et al, 2017;Basel-Vanagaite et al, 2017;Moyses-Oliveira et al, 2018). Recently, Poreau et al described unrelated patients with 70and 146-kbp microdeletions in Xq22.3 affecting TMEM164 and AMMECR1, providing novel evidence for involvement of AMMECR1 in the ATS-ID phenotype (Poreau et al, 2019).…”

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“…In case of ATS-ID, exome sequencing analyses provided data connecting missense and nonsense pathogenic variants in AMMECR1 with occurrence of elliptocytosis, cardiac and bone defects, ID, and midface hypoplasia (Andreoletti et al, 2017;Basel-Vanagaite et al, 2017;Moyses-Oliveira et al, 2018). Recently, Poreau et al described unrelated patients with 70and 146-kbp microdeletions in Xq22.3 affecting TMEM164 and AMMECR1, providing novel evidence for involvement of AMMECR1 in the ATS-ID phenotype (Poreau et al, 2019).…”