MEIS2 sequence variant in a child with intellectual disability and cardiac defects: Expansion of the phenotypic spectrum and documentation of low-level mosaicism in an unaffected parent.

Deletions and pathogenic sequence variants in Myeloid Ecotropic Insertion Site 2 (MEIS2) gene have been reported to cause a recognizable triad of intellectual disability, congenital heart malformations, and palatal defects. To date, 18 individuals with de novo pathogenic sequence variants in MEIS2 have been reported in the literature, most with all three cardinal features. We recently saw a young boy, almost 3 years of age, who was known to have mosaic XYY syndrome (47,XYY [23]/46,XY[7]). He presented with atrial and ventricular septal defects, developmental delay, facial dysmorphism, gastroesophageal reflux, undescended testicle, a buried penis with penoscrotal transposition, primary neutropenia, and a branchial cleft sinus. Whole-exome sequencing identified a previously reported in-frame pathogenic deletion (c.998_1000delGAA; p.R333del; NM_170674.4) in MEIS2. His unaffected father was confirmed to have low-level mosaicism for the same MEIS2 variant. The proband represents the 19th reported individual with a pathogenic sequence variant in MEIS2 and expands the phenotypic spectrum to include primary neutropenia, branchial anomalies, and complex genital anomalies. Furthermore, to our knowledge this is the first reported case of mosaicism for a variant in this gene in an apparently unaffected parent. This finding would have implications for recurrence risk counseling for families.

[48,XXYY syndrome: A report of four cases].

OBJECTIVE: To explore the clinical characteristics and prognosis of the 48,XXYY syndrome and gain a deeper insight into this condition. METHODS: This retrospective study included 4 cases of 48,XXYY syndrome confirmed between 2011 and 2018. We analyzed the general information, clinical manifestations, laboratory results, imaging features and outcomes of assisted reproductive technology (ART) of the patients and reviewed the relevant literature. RESULTS: The 4 patients with 48,XXYY syndrome were characterized by low literacy, soft texture and small volume of the testis, high levels of FSH and LH, and low level of serum T. Two of them were diagnosed with ejaculatory dysfunction and aspermia, and the other 2 with normal ejaculatory function but azoospermia. Biochemical analysis of seminal plasma indicated normal quantifications of both fructose and neutral α glucosidase. ART with donor sperm was performed for all the 4 cases and 3 of them got full-term babies. CONCLUSIONS: The 48,XXYY syndrome is often complicated by hypergonadotropic hypogonadism, with the clinical manifestations of aspermia or non-obstructive azoospermia. ART with donor sperm can be employed to help the patient with 48,XXYY syndrome get their non-biological offspring.

Testicular function in boys with 47,XYY and relationship to phenotype.

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross-sectional study aimed to assess testicular function serum biomarkers, including total testosterone, inhibin B, and anti-mullerian hormone (AMH), in 82 boys with XYY (11.3 ± 3.8 years) compared with 66 male controls (11.6 ± 3.8 years). The association of testicular hormones with physical features, neuropsychological phenotype, and magnetoencephalography (MEG) was assessed with multiple linear regression models. Results indicate males with XYY have significantly lower inhibin B (median 84 pg/ml vs. 109 pg/ml, p = .004) and higher AMH (median 41 ng/ml vs. 29 ng/ml, p = .011); however, testosterone, testicular volume, and stretched penile length were not different from controls. In the exploratory analysis of relationships between hormone concentrations and phenotypic assessments, higher inhibin B concentrations were positively correlated with lower BMI and better cognitive, academic, and behavioral outcomes in the XYY group. Testosterone concentrations were positively associated with better behavioral outcomes in boys with XYY. Higher testosterone and inhibin B concentrations were also associated with shorter auditory latencies measured using magnetoencephalography (MEG) in XYY. With a few exceptions, testicular hormones were not associated with phenotypic outcomes in controls. In conclusion, there is evidence of subtle impaired testicular function in boys with XYY and a newly described relationship between measures of testicular function and some aspects of the XYY phenotype.

The epidemiology of sex chromosome abnormalities.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

Gonadal dysfunction and beyond: Clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome.

Klinefelter syndrome (KS) is the most frequent sex chromosomal aneuploidy. The karyotype 47,XXY originates from either paternal or maternal meiotic nondisjunction during gametogenesis. KS males are very likely to exhibit marked gonadal dysfunctions, presenting both in severely attenuated spermatogenesis as well as hypergonadotropic hypogonadism. In addition, neurocognitive and psychosocial impairments, as well as cardiovascular, metabolic and bone disorders are often found in KS and might explain for an increased morbidity/mortality. All conditions in KS are likely to be induced by both gene overdosage effects resulting from supernumerary X-chromosomal genes as well as testosterone deficiency. Notwithstanding, the clinical features are highly variable between KS men. Symptoms can become obvious at infancy, childhood, or adolescence. However, the majority of KS subjects is diagnosed during adulthood. KS adolescents require specific attention regarding pubertal development, in order to exploit their remaining fertility potential and allow for timely and tailored testosterone replacement. The chances for sperm retrieval might decline with age and could be hampered by testosterone replacement; therefore, cryostorage of spermatozoa is an option during adolescence, before the decompensation of endocrine and exocrine testicular functions becomes more overt. Sperm from semen or surgically retrieved, in combination with intracytoplasmic sperm injection enables KS males to become biological fathers of healthy children. The aim of this article is to present the current knowledge on KS, to guide clinical care and to highlight research needs.

Meiotic Behavior of Extra Sex Chromosomes in Patients with the 47,XXY and 47,XYY Karyotype and Its Ultimate Consequences for Spermatogenesis.

Infertility is one of the most important and burning issues in present times, as a marked increase in the frequency of infertile cases has been observed all over the world. Chromosomal aneuploidy is among the known factors associated with infertility, and among sex chromosome aneuploidies, 47,XXY and 47,XYY constitute the most common class of chromosome abnormality in human live births. Considerable attention has been given to the somatic abnormalities associated with these conditions, but less is known about their meiotic progression; that is, how sex chromosome imbalance influences the meiotic process. It has been documented that men with the same underlying genetic cause of infertility do not present with uniform pathology, so it is informative to find out how meiotic progression differs in patients with similar chromosomal aneuploidy having different phenotypes. The importance of studying meiotic progression in patients with sex chromosome abnormalities has increased many fold with the introduction of assisted reproductive technologies that have made it possible for infertile men to become biological parents. Hence, exploring the possible consequences of sex chromosome aneuploidy for meiotic chromosome segregation is worthwhile. The objective of this review, in the context of current knowledge, is to discuss problems associated with fertility and progression of meiosis in two relatively common sex chromosome aneuploidies, 47,XXY and 47,XYY, reported in humans.

Current survey of early childhood intervention services in infants and young children with sex chromosome aneuploidies.

Sex chromosome aneuploidies (SCAs) are the most commonly occurring aneuploidies in children with a collective prevalence rate of 1 in 500 live births. Prior research has documented SCAs are associated with an increased risk for early expressive language and gross motor delays, learning disorders, ADHD, autism spectrum disorder, anxiety, and executive function problems. Although SCAs have been historically underdiagnosed in young children, recent advances in noninvasive prenatal testing have resulted in an increasing nationwide cohort of infants with confirmed diagnoses. Consequently, early childhood support systems must prepare for an influx of children with known risks for associated developmental delays and potential school problems. This national survey aimed to update our understanding of current early childhood intervention services for young children with SCA in the United States and to describe parent perspectives and priorities. Descriptive statistics, chi-square tests, and logistic regression models controlling for parent education revealed a majority of respondents reported receiving public early childhood intervention services with speech therapy as the most common service. There were significant differences in early childhood intervention services by timing of diagnosis (prenatal vs. postnatal), number of sex chromosomes (trisomy vs. tetra/pentasomy), and geographic location. Parents described interventions as desirable and effective yet also difficult to obtain due to issues with the SCA phenotype, lack of provider knowledge, and challenges navigating the intervention systems. Results support the need for enhanced provider training in SCAs, policy change for early childhood intervention qualification criteria for SCA conditions, and collaboration between medical and early childhood settings.

A patient with 46,XY/47,XYY karyotype and female phenotype: a case report.

BACKGROUND: 47,XYY is a chromosomal abnormality syndrome that is typically observed in patients with a male phenotype. Few patients with XYY syndrome will have infertility. We here report a case of 46,XY/47,XYY syndrome diagnosed in a patient with a female phenotype. CASE PRESENTATION: A 15-year-old patient with a female phenotype visited our hospital owing to a chief complaint of short stature as of the age of 6 years. She was diagnosed with dwarf syndrome at the age of 10, but no change was noted after 2 months of growth hormone treatment. The patient's height was 136 cm and the weight was 29 kg, both of which were below the third percentile for her age/gender. In addition to short stature, the 4th and 5th metacarpals were short and there was no significant sex development. Karyotype analysis showed 47,XYY, and chromosomal microarray examination showed a chimera of 46,XY/47,XYY. CONCLUSION: This is an extremely rare case of 47,XYY abnormality in a patient with a female phenotype, with only one such known case reported previously. Since the cause is unknown, and symptoms of this syndrome are highly atypical and variable in childhood, clinicians should be aware of this possibility to avoid misdiagnosis and offer counseling and hormone therapy as needed to patients and their parents to improve their quality of life.

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Molecular characterisation of a case of dicentric Y presented as nonobstructive azoospermia with testicular early maturation arrest.

The dicentric Y chromosome is the most common cytogenetically visible structural abnormality of Y chromosome. The sites of break and fusion of dicentric Y are variable, but break and fusion at Yq12 (proximal to the pseudoautosomal region 2/PAR 2) is very rare. Dicentric Y chromosome is unstable during cell division and likely to generate chromosomal mosaicism. Here, we report a case of infertile male with nonmosaic 46,XY where chromosome Y was dicentric with break and fusion at Yq12 (proximal to PAR 2). Clinical presentation of the case was nonobstructive azoospermia due to early maturation arrest at the primary spermatocyte stage. Various molecular techniques such as FISH, STS-PCR and DNA microarray were carried out to characterise genetic defect leading to testicular maturation arrest in the patient. The break and fusion was found at Yq12 (proximal to PAR 2) and resulted in near total duplication of Y chromosome (excluding PAR 2). The reason for maturation arrest seems due to CNVs of PARs (gain in PAR 1 and loss of PAR 2) and azoospermia factors (gain).

Noninvasive prenatal screening for fetal common sex chromosome aneuploidies from maternal blood.

Objective To explore the feasibility of high-throughput massively parallel genomic DNA sequencing technology for the noninvasive prenatal detection of fetal sex chromosome aneuploidies (SCAs). Methods The study enrolled pregnant women who were prepared to undergo noninvasive prenatal testing (NIPT) in the second trimester. Cell-free fetal DNA (cffDNA) was extracted from the mother's peripheral venous blood and a high-throughput sequencing procedure was undertaken. Patients identified as having pregnancies associated with SCAs were offered prenatal fetal chromosomal karyotyping. Results The study enrolled 10 275 pregnant women who were prepared to undergo NIPT. Of these, 57 pregnant women (0.55%) showed fetal SCA, including 27 with Turner syndrome (45,X), eight with Triple X syndrome (47,XXX), 12 with Klinefelter syndrome (47,XXY) and three with 47,XYY. Thirty-three pregnant women agreed to undergo fetal karyotyping and 18 had results consistent with NIPT, while 15 patients received a normal karyotype result. The overall positive predictive value of NIPT for detecting SCAs was 54.54% (18/33) and for detecting Turner syndrome (45,X) was 29.41% (5/17). Conclusion NIPT can be used to identify fetal SCAs by analysing cffDNA using massively parallel genomic sequencing, although the accuracy needs to be improved particularly for Turner syndrome (45,X).

Frontal Aslant Tract Abnormality on Diffusion Tensor Imaging in an Aphasic Patient With 49, XXXXY Syndrome.

BACKGROUND: The karyotype 49, XXXXY is one of the most severe forms of chromosome aneuploidy and is characterized clinically by developmental delay and profound language impairment, particularly involving expressive language functions. We describe the neurocognitive profile and structural anatomy of language pathway in a 2-year-old boy with 49, XXXXY syndrome with expressive aphasia. METHODS: Retrospective chart review of the patient was performed. We characterized the language deficits using neuropsychologic testing. We further studied the language pathways using diffusion tensor imaging analytical technique. RESULTS: The neurocognitive profile of the patient showed relative weakness of expressive language skills compared with other domains. Diffusion tensor imaging analysis demonstrated a poorly developed frontal aslant tract, a weak indirect segment of arcuate fasciculus, and normally developed direct segment of arcuate fasciculus. The frontal aslant tract is a novel pathway that connects the Broca's area with the anterior cingulate and presupplementary motor area and plays a role in the "motor stream" of language. CONCLUSION: A poorly developed frontal aslant tract may underlie the expressive language deficits and provide some insight into the role of X chromosome in modulating the development of language tracts.

A study of aneuploidy and DNA fragmentation in spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line.

Meiotic segregation of mosaic males with a 45,X cell line has been little examined. In this study, we evaluated the risk of aneuploid gametes using fluorescence in situ hybridization (FISH) and DNA fragmentation in ejaculated spermatozoa of three men with sex chromosome mosaicism including a 45,X cell line. Triple- and dual-color FISH were performed. Sperm DNA fragmentation was detected using the TUNEL assay. A significantly increased frequency of XY disomic spermatozoa was observed for patients (P)1 and P2. A significant increase in diploidy and autosomal aneuploidy was found in P2 and P3, respectively. The rate of DNA fragmentation was not different from that observed in a control group. Data from the literature are scarce (only 3 cases reported), making comparison of the present data difficult, especially as the frequencies of the cell lines comprising the mosaicism differed between patients. Furthermore, the proportion of the different cell lines can differ from one tissue to another in the same patient. Whether the relative levels of the several cell lines present in the mosaicism can influence the rate of aneuploid spermatozoa remains unknown.

Brain morphology in children with 47, XYY syndrome: a voxel- and surface-based morphometric study.

The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y-chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y-chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age-matched healthy controls by combining voxel-based morphometry (VBM) and surface-based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y-chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas.

Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies.

OBJECTIVE: The 45,X/46,XY and 45,X/47,XYY group of patients includes some of those previously diagnosed with 'mixed gonadal dysgenesis'. Our aim was to establish the clinical and gonadal spectrum, and early surgical management, of patients with chromosomal mosaicism presenting with genital anomalies. PATIENTS AND METHODS: We performed a retrospective review of patients with 45,X/46,XY or 45,X/47,XYY mosaicism presenting with genital ambiguity between 1988 and 2009. At least one gonadal biopsy or gonadectomy specimen was available for each patient. Gonadal histology was re-evaluated by a paediatric pathologist. RESULTS: Of 31 patients with 45,X/46,XY (n = 28) or 45,X/47,XYY (n = 3) mosaicism and genital anomalies, 19 (61%) were raised male. Histology of 46 gonads was available from patients who had undergone a gonadectomy or gonadal biopsy, at a median age of 9.5 months. 18 gonads were palpable at presentation, including 5 (28%) histologically unremarkable testes, 2 streak gonads, and 1 dysgenetic gonad with distinct areas of testicular and ovarian stroma but no oocytes. All intra-abdominal gonads were found to be dysgenetic testes (of which 2 were noted to have pre-malignant changes) or streaks, apart from 1 histologically unremarkable testis. 15 (48%) patients had other anomalies, most commonly cardiac and renal; 4 (13%) had a Turner phenotype. CONCLUSION: The anatomy and gonadal histology of 45,X/46,XY and 45,X/47,XYY individuals with genital ambiguity do not conform to a set pattern, and hence management of each patient should be individualized according to detailed anatomical and histological assessment.

Sex chromosomes and the brain: a study of neuroanatomy in XYY syndrome.

AIM: To assess global and regional brain matter variations associated with XYY syndrome by comparison with Klinefelter syndrome and typical development. METHODS: We used two conceptually distinct voxel-based magnetic resonance imaging methods to examine brain structure in young males with XYY syndrome: (1) volumetric comparison to assess global grey and white matter volumes and (2) support vector machine-based multivariate pattern classification analysis to assess regional neuroanatomy. We assessed verbal, non-verbal, and spatial abilities with the Differential Ability Scales (DAS), and we measured autism diagnostic criteria in eight males with XYY syndrome using the Social Responsiveness Scale and the Autism Diagnostic Interview-Revised (ADI-R). RESULTS: A comparison of 36 typically developing males (mean age 11 y, SD 1 y 9 mo), 31 males with Klinefelter syndrome (mean age 9 y 8 mo, SD 1 y 8 mo), and eight males with XYY syndrome (mean age 11 y 6 mo, SD 1 y 11 mo) showed that total white and grey matter volumes were significantly, or nearly significantly, higher in males with XYY syndrome than in males belonging to the other two groups (grey matter: XYY males vs typically developing males, p<0.006; XYY vs males with Klinefelter syndrome, p<0.001; white matter: XYY males vs typically developing males, p=0.061; XYY males vs males with Klinefelter syndrome, p=0.004). Voxel-based multivariate pattern classification analysis indicates that, after controlling for global volumes, regional brain variations in XYY syndrome are more like those found in Klinefelter syndrome than those occurring in typical development. Further, visualization of classification parameters suggests that insular and frontotemporal grey matter and white matter, including known language areas, are reduced in males with XYY syndrome, similar to what is seen in Klinefelter syndrome. In males with XYY syndrome, DAS verbal and non-verbal scores were significantly lower than in typically developing participants (both p<0.001). DAS scores were not significantly different between XYY and Klinefelter syndrome groups. In five of eight males with XYY syndrome, the Social Responsiveness Scale score exceeded the cut-off for a likely diagnosis of autism spectrum disorder (ASD). In three of eight males with XYY syndrome, the ADI-R score met the cut-off for ASD diagnosis; in another two, ADI-R scores within the social and communication domains met the cut-off values for a diagnosis of ASD. INTERPRETATION: The results suggest that genetic variations associated with XYY syndrome result in increased brain matter volumes, a finding putatively related to the increased frequency of ASDs in individuals with this condition. In addition, frontotemporal grey and white matter reductions in XYY syndrome provide a likely neuroanatomical correlate for observed language impairments.

Presence of spermatogonia in 47,XXY men with no spermatozoa recovered after testicular sperm extraction.

OBJECTIVE: To evaluate the presence of spermatogonia in men diagnosed with Klinefelter syndrome (KS), in whom no testicular spermatozoa were recovered by testicular sperm extraction. DESIGN: Retrospective case series. SETTING: University hospital. PATIENT(S): Testicular samples from 22 nonmosaic 47,XXY men, aged 24-43 years, with no spermatozoa at multiple biopsies. INTERVENTION(S): Paraffin-embedded testicular tissue was sectioned and stained with hematoxylin-eosin, and immunostainings were performed for both MAGE-A4 and vimentin. MAIN OUTCOME MEASURE(S): The presence of spermatogonia. RESULT(S): Massive fibrosis and hyalinization were observed in all men with KS. Spermatogonia were observed in 4 of 22 men with KS, with differentiation up to the spermatocyte level in 2 of them. CONCLUSION(S): A few men with KS, having no spermatozoa after testicular sperm extraction, still had few spermatogonia. These patients may eventually benefit from in vitro maturation using spermatogonial stem cells. The adult KS population can thus be divided into three subgroups: one subgroup showing focal spermatogenesis, a second having spermatogonia, and a third group in which no germ cells can be recovered. Further research is necessary to unravel the mechanism leading to these different patterns in patients with KS.

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions.

BACKGROUND: X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. METHODS: Array CGH analysis was performed using chromosomal microarray with ∼105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. RESULTS: A novel ∼0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. CONCLUSIONS: The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.

Cryptic x; autosome translocation in a boy--delineation of the phenotype.

Chromosome X-to-autosome translocations [t(X;A)] are rare rearrangements with an estimated occurrence of 1 to 3 per 10,000 live births. Occurrences of Xq duplications have been observed in male and female subjects in whom the X chromosome segment escapes inactivation and results in functional disomy. We report a case of X;6 translocation in a 7-year-old boy with severe mental retardation, hypotonia, and recurrent respiratory tract infections. High-resolution chromosome analyses (fluorescence in situ hybridization, multiplex ligation probe-dependent amplification, and whole-genome array) revealed a terminal duplication of chromosome X at q28-qter (approximately 3.246 Mb in size) involving gene MECP2 and a terminal deletion (approximately 1.89 Mb) with the breakpoint at 6q27. This is the second report of a boy with a cryptic unbalanced Xq-autosome translocation. This case increases our understanding of mental disability caused by terminal Xq duplication.