X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. A cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. The uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). Using deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies. We investigated whether the parental origin of the extra X chromosome (POX) in Klinefelter syndrome (XXY/KS) affects cognitive, behavioral, and structural brain traits. Our study included 58 people with XXY/KS and used a new method to determine whether the extra X came from the mother (POXm) or father (POXp). Despite previous mixed results, our study found no significant differences in cognitive or behavioral traits based on POX. Imaging revealed some differences in surface area in 2 brain regions, but these findings were limited and require further research. Overall, our study suggests that POX has minimal impact on XXY/KS characteristics.

We presented in this article a patient with Klinefelter syndrome (KS) (47,XXY) who had maternal nondisjunction and uniparental disomy of the X chromosome with regions of heterodisomy and isodisomy, an interstitial Xp22.31 deletion of both X chromosomes, and other problems. His mother also possesses the same Xp22.31 deletion. The patient presented with status epilepticus and stroke, followed by severe brain atrophy and developmental regression. His unusual clinical and cytogenetic findings apparently have not been reported with either KS or Xp22.31 deletions. Based on the patient's available genetic and biochemical information, we cannot satisfactorily explain his seizures, strokes, or catastrophic brain regression.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, especially in males. Females with FXS tend to be relatively mildly affected because of compensation by a second X chromosome with a normal FMR1 gene. In most cases, FXS is caused by an expansion of the CGG repeats (>200 triplets, full mutation, FM) in the 5'-untranslated region of the FMR1 gene. Premutation alleles (PM, 55-200 repeats), usually lack the clinical features of FXS, are highly unstable when transmitted to offspring and can give rise to FM, especially in female meiosis. We describe a 3-year-old girl with typical FXS, with only a fully expanded FMR1 allele (288 CGG repeats) due to uniparental isodisomy of X chromosome, inherited from mother carrying a premutation allele. The patient's FMR1 methylation region is completely methylated due to full mutation of CGG repeat. This unusual and rare case indicates the importance of a detailed genomic approach to explain nontraditional Mendelian inheritance pattern.

Noninvasive prenatal testing accurately detects trisomy for chromosomes 13, 21, and 18, but has a significantly lower positive predictive value for monosomy X. Discordant monosomy X results are often assumed to be due to maternal mosaicism, usually without maternal follow-up. We describe a case of monosomy X-positive noninvasive prenatal testing that was discordant with the 46,XX results from amniocentesis and postnatal testing. This monosomy X pregnancy doubled the single X chromosome, leading to 45,X/46,XX mosaicism in the placenta and uniparental isodisomy X in the amniotic fluid. Thus, at least some discordant monosomy X results are due to true mosaicism in the pregnancy, which has important implications for clinical outcome and patient counseling.

Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter→q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS.