Xq25 Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome. One patient with triplication of Xq25 has been reported.

Description

Xq25 duplication syndrome is an X-linked neurodevelopmental disorder characterized by delayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features. Additional variable features may include thin corpus callosum on brain imaging and sleep disturbances. Carrier females may be mildly affected (summary by Leroy et al., 2016).

Clinical Features

Philippe et al. (2013) reported 2 unrelated males with delayed development, intellectual disability, speech delay, behavioral abnormalities, and hypotonia associated with an Xq25 duplication identified by array CGH. The first patient was a 24-year-old man previously reported in a large study of patients with autism (Jacquemont et al., 2006), and the second patient was a 4-year-old boy. Both patients had overlapping mildly dysmorphic facial features, including hypotonic face, epicanthal folds, malar flatness, thick vermilion of the lips, lower palpebral eversion, and prognathism, as well as thin corpus callosum on brain imaging. Both patients also had sleep disturbances. The sizes of the duplications were 1.2 and 5.02 Mb, respectively, and included the GRIA3 (305915), XIAP (300079), and STAG2 (300826) genes. Both mothers and the maternal grandmother of the second patient also carried the duplications and showed skewed X inactivation (89 to over 90%). The mother of the second patient had mild intellectual disability on testing.

Leroy et al. (2016) reported 5 brothers and an unrelated male with Xq25 duplication syndrome. The patients underwent array CGH because of developmental delay and/or intellectual disability. All boys had moderate intellectual disability, speech disturbances, and sleep disturbances; 4 had behavioral issues and 3 had hypotonia. Common, but variable, dysmorphic features included hypotonic facies (5/6), lower palpebral eversion (6/6), epicanthal folds (3/6), sparse or arched eyebrows (4/6), malar flattening (5/6), and thick vermilion of the lips (5/6). The 2 mothers were considered mildly affected with learning disabilities; one of the mothers had seizures, but none of the boys had seizures. The size of the duplication was 662 kb in the brothers and 465 kb in the unrelated patient; combined with data from previous reports of Xq25 duplication, the common region of overlap was 173 kb and included only the STAG2 gene. X-inactivation studies in the 2 mothers showed moderate skewed X-inactivation patterns (13/87 in one mother and 18/82 in the other). Leroy et al. (2016) noted that the STAG2 protein is a subunit of the cohesin complex, which is a proteinaceous ring that surrounds chromatin and regulates the separation of sister chromatids into 2 daughter cells during cell division.

Kumar et al. (2015) reported 28 males, including 15 from 6 unrelated families and 13 singleton cases, with intellectual disability associated with Xq25 microduplications and 1 case with a microtriplication. The initial 6 families were ascertained by array CGH and X-chromosome exome sequencing. The duplication/triplications were all different sizes and ranged from 202 to 746 kb long. The additional 13 singleton cases were found from a large cohort of about 27,000 males with neurodevelopmental delay and/or congenital anomalies who underwent array CGH. The critical region in all patients included the STAG2 gene, and most included at least part of the neighboring XIAP gene. All males with Xq25 duplications presented with some degree of intellectual disability, and most (68%) had behavioral problems, such as anxiety, hyperactivity, and aggressive behavior; autism spectrum disorder was reported in 4 patients. Brain imaging, performed in 10 individuals, was normal in 4 and showed nonspecific abnormalities in 6, such as cerebellar vermis hypoplasia and thin corpus callosum. Most patients had a subtle but consistent dysmorphic facial phenotype, including malar flatness, full lips, and prognathia; several (21%) had short stature. Ten (32%) had seizures. Of the 10 carrier females, 1 had mild intellectual disability, 6 had borderline intellectual disability or developmental delay, and 3 had normal cognition.

Xq25 Triplication

Kumar et al. (2015) identified 1 male (family SA1) with a triplication of Xq25, including the XIAP and STAG2 genes. He had a more severe phenotype compared to those with Xq25 duplications. He had severe ID, stereotypies, obsessive-compulsive behavior, anxiety, and aggressive outbursts. Dysmorphic features included broad forehead, frontal bossing, small posteriorly rotated low-set ears, long nose, smooth philtrum, widely spaced teeth, gum hypertrophy, facial hypotonia, and short distal phalanges of fingers. Brain imaging showed mild cerebral ventricular enlargement. The patient's mother, who had 4 copies of the region, had slightly skewed X inactivation (85:15) and had borderline intellectual disability and schizophrenia.

Molecular Genetics

In lymphoblastoid cells derived from affected individuals with Xq25 duplication, Kumar et al. (2015) found increased expression of the STAG2 gene, with increased mRNA levels of XIAP and THOC2 in those whose regions included those genes. Western blot analysis showed increased STAG2 protein in all patients, but normal THOC2 protein levels in those with THOC2 gene duplication. XIAP was also increased, but 1 patient had normal XIAP protein levels, suggesting to the authors that copy number gains of STAG2 alone is responsible for the phenotype. Patient cells showed dysregulation of genes expressed in the central nervous system, some of which have been implicated in neurologic disorders with intellectual disability, notably OPHN1 (300127).