10-year-old female with intragenic KANSL1 mutation, no KANSL1-related intellectual disability, and preserved verbal intelligence.

Koolen-de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild-to-moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder. This case expands the mild end of the neurodevelopmental spectrum seen in children with de novo KANSL1 mutation and KdVS. © 2017 Wiley Periodicals, Inc.

The benefits and limitations of cell-free DNA screening for 47, XXY (Klinefelter syndrome).

OBJECTIVE: The purpose of this paper is to provide an overview of the 47, XXY syndrome, which is the most commonly occurring X and Y chromosomal variation. This paper seeks to review what is currently known of noninvasive prenatal testing (NIPT) and 47, XXY and investigate potential risks and benefits of prenatal identification. METHOD: A literature review of NIPT and 47, XXY was performed to identify limitations of current NIPT techniques. RESULTS: As NIPT becomes an increasingly more routine procedure, prenatal findings of 47, XXY may increase. Awareness of this disorder and appropriate genetic counseling is necessary. CONCLUSION: X and Y chromosomal variations will be identified through this screening, and the benefits and limitations to this finding need to be thoughtfully considered. © 2017 John Wiley & Sons, Ltd.

Neurodevelopmental variability in three young girls with a rare chromosomal disorder, 48, XXXX.

Fourty eight, XXXX is a rare chromosomal aneuploidy associated with neurocognitive deficits, speech and language disorders and executive dysfunction but the scarcity and variability of reported cases limit our understanding of the 48, XXXX phenotype. To our knowledge, this is the first study to report on the neurodevelopmental profile of three young females with 48, XXXX. Patient 1 (age = 11.0), Patient 2 (age = 10.9), and Patient 3 (age = 6.4) were evaluated using comprehensive neurodevelopmental assessments. Parent questionnaires were completed to assess behavioral and psychosocial domains including executive function, ADHD and anxiety. Nonverbal intelligence quotients were 56, 80, and 91 for Patients 1, 2, and 3, respectively. There were significantly impaired visual motor capacities in graphomotor and perceptual domains below the 5th centile in Patients 1 and 2, and mildly impaired visual perception skills in Patient 3. All three patients had Childhood Apraxia of Speech (CAS) but of varying severity and similar executive dysfunction, externalizing problems and social difficulties. Familial learning disabilities (FLD) in Patient 1 and the co-occurrence of ADHD in Patient's 1 and 2 may contribute to their more impaired cognitive performances relative to Patient 3 who is the second reported case of 48, XXXX to have normal intellect. These distinct and overlapping characteristics expand the phenotypic profile of 48, XXXX and may be used in the counseling of families and treatment of children with 48, XXXX.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

The human inactive X chromosome modulates expression of the active X chromosome.

The "inactive" X chromosome (Xi) has been assumed to have little impact, in trans, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis, through Xi-wide transcriptional attenuation, and in trans, through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

The association between maternal occupation and down syndrome: A report from the national Down syndrome project.

BACKGROUND: Among live births, Down syndrome (DS) due to trisomy 21 is the most commonly occurring autosomal trisomy, typically resulting from meiotic nondisjunction. Currently, advanced maternal age and altered recombination patterns are the only well-known risk factors for nondisjunction. Maternal occupation has not been investigated as a risk factor for maternally-derived cases of trisomy 21. OBJECTIVES: This study explored the association between maternal occupation and chromosome 21 nondisjunction, stratified by the stage of maternal error - either Meiosis I (MI) or Meiosis II (MII). Additionally, we investigated specific toxic agents associated with occupation classes. METHODS: Using narrative job descriptions from the National Down Syndrome Project (NDSP), a population-based case-control study, occupation was coded using the 2010 Standard Occupational Classification (SOC). Odds ratios were calculated for the association between occupation class and having a child with DS, stratified by meiotic stage. An exposure analysis was performed within occupational classes that were statistically significant predictors of having a child with DS. Odds ratios were calculated to analyze associations between individual exposures and having a child with DS. RESULTS: The odds of MII nondisjunction were increased among Production Workers (OR = 3.15; 95%CI = 1.52,6.55). Women who worked as Life, Physical and Social Scientists or in Food Preparation and Serving-Related Occupations experienced greater likelihood of MI errors (OR = 5.72(1.80,18.20), and OR = 1.87(1.08,3.24), respectively). Exposure to solvents within the Production Worker group was a significant predictor (p < 0.05) for MI nondisjunction. No other environmental agents had a significant association with nondisjunction. DISCUSSION: Specific maternal occupation classes were associated with MI and MII chromosome 21 nondisjunction. These occupation classes were selected for an exposure analysis, which determined solvents as highly predictive of MI nondisjunction among Production Workers. Findings from this analysis will serve to further explore the relationship between maternal occupation and chromosome 21 nondisjunction.