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Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome
Author(s) -
Cordeddu Viviana,
Macke Erica L.,
Radio Francesca Clementina,
Lo Cicero Stefania,
Pantaleoni Francesca,
Tatti Massimo,
Bellacchio Emanuele,
Ciolfi Andrea,
Agolini Emanuele,
Bruselles Alessandro,
BrunettiPierri Nicola,
Suri Mohnish,
Josephs Katherine S.,
McEntagart Meriel,
Lanpher Brendan,
Nickels Katherine C.,
Haworth Andrea,
Reed Laura,
Cappuccio Gerarda,
Mammi Isabella,
Tarnowski Jessica M.,
Novelli Antonio,
Melis Daniela,
Callewaert Bert,
Dallapiccola Bruno,
Klee Eric,
Tartaglia Marco
Publication year - 2020
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13775
Subject(s) - missense mutation , phenotype , genetics , speech delay , biology , epilepsy , intellectual disability , endocrinology , medicine , gene , neuroscience
UBE2A deficiency, that is, intellectual disability (ID) Nascimento type (MIM 300860), is an X‐linked syndrome characterized by developmental delay, moderate to severe ID, seizures, dysmorphisms, skin anomalies, and urogenital malformations. Forty affected subjects have been reported thus far, with 31 cases having intragenic UBE2A variants. Here, we report on additional eight affected subjects from seven unrelated families who were found to be hemizygous for previously unreported UBE2A missense variants (p.Glu62Lys, p.Arg95Cys, p.Thr99Ala, and p.Arg135Trp) or small in‐frame deletions (p.Val81_Ala83del, and p.Asp101del). A wide phenotypic spectrum was documented in these subjects, ranging from moderate ID associated with mild dysmorphisms to severe features including congenital heart defects (CHD), severe cognitive impairment, and pineal gland tumors. Four variants affected residues (Glu62, Arg95, Thr99 and Asp101) that contribute to stabilizing the structure of the E3 binding domain. The three‐residue in‐frame deletion, p.Val81_Ala83del, resulted from aberrant processing of the transcript. This variant and p.Arg135Trp mapped to regions of the protein located far from the E3 binding region, and caused variably accelerated protein degradation. By reviewing available clinical information, we revise the clinical and molecular profile of the disorder and document genotype‐phenotype correlations. Pineal gland cysts/tumors, CHD and hypogammaglobulinemia emerge as recurrent features.