Functional disomy of proximal Xp causes a distinct phenotype comprising early hypotonia, hypertelorism, small hands and feet, ear abnormalities, myopia and cognitive impairment

Abstract

Extra structurally abnormal chromosomes (ESACs) derived from the X chromosome are rare. We report a non-mosaic ESAC derived from the X chromosome in a 3-year-old female who presented with early hypotonia, developmental delay, hypertelorism, low set ears, and small hands and feet. The breakpoints of the ESAC were mapped by SNP microarray to Xp11.1-p11.22, a region encompassing 7.17 Mb and containing 110 known or putative genes and excluding the X-inactivation center. A review of other reported patients with karyotypes that cause functional disomy of proximal Xp allows delineation of a common phenotype comprising early hypotonia, cognitive impairment, hypertelorism, myopia, small hands and feet and abnormal external ears.

Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

“…Indeed, the patient presents with the key phenotypic features related to Xp functional disomy as described by Hunter et al [2009]: cognitive impairment, hypotonia, hypertelorism, and ear abnormalities. Considering the 59 genes duplicated, it is difficult to obtain a precise genotype/phenotype correlation for each phenotypic trait as it has already been the case in similar findings of large Xp functional disomies [Lintas et al, 2016].…”

A de novo duplication of Xp11.22–p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome

“…Our patient has had no seizures since the age of 2.5 years and remains seizure free without antiepileptic medication at the age of 8 years, supporting the hypothesis of Giorda et al 2009 that the seizures and EEG paroxysms may be confined to preadolescence. Interestingly, seizures were not a feature in the patients described with duplications that are either centromeric [Froyen et al, 2007; Hunter et al, 2009] or telomeric [Monnot et al, 2008] to the synaptophysin ( SYP —OMIM*313475) gene (∼48.9 Mb, Fig. 3).…”

“…Five of these patients have relatively large duplications with the distal breakpoint within or beyond Xp21.2 [Nielsen and Langkjaer, 1982; Tuck‐Muller et al, 1993; Matsuo et al, 1999; Portnoi et al, 2000; Kokalj Vokac et al, 2002]. In other patients, the duplicated segment has been confined to bands p11.22 and p11.23 [Giorda et al, 2009; Hunter et al, 2009]. We present a girl with a duplication of Xp11.22–p11.4 who has speech delay, epilepsy, intellectual disability, and skewed X inactivation.…”

A Rare Combination of Functional Disomy Xp, Deletion Xq13.2-q28 Spanning the XIST Gene, and Duplication 3q25.33-q29 in a Female with der(X)t(X;3)(q13.2;q25.33)

“…Features of functional disomy Xp include early hypotonia, intellectual disability, hypertelorism, myopia, small hands and feet, and external ear malformations, while clinical features of duplication 3q syndrome include characteristic facial dysmorphism, hirsutism, microcephaly, intellectual disability, genitourinary anomalies, sacrococcygeal teratoma, hand and feet abnormalities, renal and congenital heart defects. 2,3,[9][10][11][12][13][14][15][16] Deletions of Xq result in Turner's syndrome with clinical features mainly including primary ovarian insufficiency. [6][7][8] Consistent with duplication 3q syndrome our patient presents with intellectual disability, sacral teratoma, neurogenic bladder, and facial dysmorphisms including downslanting palpebral fissures, bushy eyebrows, and long eyelashes.…”

“…Partial 3q duplications typically result from unbalanced rearrangements or de novo duplications, while functional disomy Xp in females can result from chromosomes containing Xp chromosomal material that lacks the XIST gene (i.e., X chromosomes with XIST deletion or autosomes harboring Xp chromosomal material). 2,3 Located within the X-inactivation center on chromosome Xq13.2, the cis-acting XIST gene encodes RNA that "coats" the X chromosome thus preventing DNA from being transcribed with the exceptions of genes that escape inactivation, most of them located in the pseudoautosomal regions 1 and 2 (PAR1 and PAR2) but also seen dispersed throughout the X chromosome. 1,4 While the normal chromosome X is preferentially silenced in balanced X-autosomal translocations, in unbalanced X-autosomal translocations the derivative chromosome X is preferentially silenced to best maintain a functionally balanced genome.…”