Delineation of Clinical Manifestations of the Inherited Xq24 Microdeletion Segregating with sXCI in Mothers: Two Novel Cases with Distinct Phenotypes Ranging from UBE2A Deficiency Syndrome to Recurrent Pregnancy Loss

Abstract

skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.

A novel UBE2A splice site mutation with intellectual disability type Nascimento

“…Thus far, only two splice-site mutations in UBE2A, seven missense mutations in UBE2A, and four larger deletions in UBE2A have been reported [7,12,[15][16][17][18][19][20][21][22][23]. Besides, all probands with UBE2A deficiency syndrome have resemblance phenotypes, including characteristic facial appearance, speech anomalies, and intellectual disability [20,24]. However, our proband found novel clinical appearance, including a typical four-finger line and erected head unstable, which has not been described in previous patients.…”

“…Notably, we report novel molecular and clinical data of this patient with intellectual disability. Thus far, only two splice-site mutations in UBE2A, seven missense mutations in UBE2A, and four larger deletions in UBE2A have been reported [7,12,[15][16][17][18][19][20][21][22][23]. Besides, all probands with UBE2A deficiency syndrome have resemblance phenotypes, including characteristic facial appearance, speech anomalies, and intellectual disability [20,24].…”

A novel UBE2A splice site variant causing intellectual disability type Nascimento

“…Till date, only two splice-site variants in UBE2A, seven missense variants in UBE2A, and four larger deletions in UBE2A have been reported. 7,[12][13][14][15][16][17][18][19][20][21] In addition, all probands with UBE2A deficiency syndrome have similar phenotypes, including characteristic facial appearance, speech anomalies, and intellectual disability. 18,22 However, the clinical presentation of our proband was novel, including a deep single transverse palmar crease and an inability to hold the head erect, which has not been described in previous patients.…”

“…Notably, we report novel molecular and clinical data of this patient with intellectual disability. Till date, only two splice‐site variants in UBE2A, seven missense variants in UBE2A, and four larger deletions in UBE2A have been reported 7,12–21 . In addition, all probands with UBE2A deficiency syndrome have similar phenotypes, including characteristic facial appearance, speech anomalies, and intellectual disability 18,22 .…”

DNA Methylation Episignatures in Neurodevelopmental Disorders Associated with Large Structural Copy Number Variants: Clinical Implications

“…Genes whose primary function is not associated with epigenetic and chromatin regulatory mechanisms, such as ubiquitin-conjugating enzyme E2 A ( UBE2A ) and spermine synthase ( SMS ) in X-linked syndromic forms of mental retardation—Nascimento and Snyder–Robinson types, respectively [ 44 ]—have also shown evidence of unique episignatures. The UBE2A gene at Xq24 encodes the RAD6 ubiquitin-conjugating enzyme and has been recently shown to be involved in histone modifications that control gene expression [ 69 , 70 ]. The SMS gene at Xp22.11 encodes for an enzyme involved in polyamine synthesis and recycling and is directly related to decarboxylated SAM.…”