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Congenital anomalies of the kidney and urinary tract (CAKUT) and congenital heart disease (CHD) are the most common congenital defects and constitute a major cause of morbidity in children. Anomalies of both systems may be isolated or associated with congenital anomalies of other organ systems. Various reports support the co‐occurrence of CAKUT and CHD, although the prevalence can vary. Cardiovascular anomalies occur in 11.2% to 34% of patients with CAKUT, and CAKUT occur in 5.3% to 35.8% of those with CHD. The co‐occurrence of genetic factors in both CAKUT and CHD would raise common etiologies including genetics, genetic‐environmental interactions, or shared molecular mechanisms and pathways such as NODAL, NOTCH, BMP, WNT, and VEGF. Studies in animal models and humans have indicated a genetic etiology for CHD and CAKUT with hundreds of genes recognized and thousands of entries, found in a catalog of human genetic disorders. There are over 80 CAKUT genes and over 100 CHD genes available for clinical testing. For example, the HNFIB gene accounts for 5% to 31% of reported cases of CAKUT. In view of the association between CAKUT and CHD, a thorough cardiac examination should be performed in patients with CAKUT, and a similar evaluation for CAKUT in the presence of CHD. This will allow early diagnosis and therapeutic intervention to improve the long‐ term outcome of patients affected, and test for at‐risk family members. We present here evidence for an association of anomalies involving the two organ systems, and discuss possible etiologies of targeted genes, their functions, biological processes and interactions on embryogenesis. [ABSTRACT FROM AUTHOR]

Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families. [ABSTRACT FROM AUTHOR]

Introduction: Prader–Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal region, generally from a paternal deletion. Predominant features include infantile hypotonia, a poor suck with failure to thrive, craniofacial features, and developmental and behavioral problems including self-injury and childhood onset of obesity. In addition to severe obesity, patients with PWS present with other symptoms of autonomic nervous system dysfunction. Methods: We examined the features seen in Prader–Willi syndrome and searched the literature for evidence of autonomic nervous system involvement in this rare obesity-related disorder and illustrative findings possibly due to autonomic nervous system dysfunction. Additionally, we reviewed the literature in relation to childhood obesity syndromes and compared those syndromes to the syndromic obesity found in Prader–Willi syndrome. Results: We report autonomic nervous system-related symptoms associated with childhood obesity impacting features seen in Prader–Willi syndrome and possibly other obesity-related genetic syndromes. We compiled evidence of both an autonomic route for the obesity seen in PWS and other autonomic nervous system-related dysfunctions. These include decreased salvation, sleep disordered breathing, increased pain and thermal threshold instability, delayed gastric emptying, altered blood pressure readings, and pupillary constriction responses as evidence of autonomic nervous system involvement. Conclusions: We summarized and illustrated findings of autonomic nervous system dysfunction in Prader–Willi syndrome and other obesity-related syndromes and genetic factors that may play a causative role in development. [ABSTRACT FROM AUTHOR]

Prader–Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside–Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. [ABSTRACT FROM AUTHOR]

A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS). Of these 154 PWS individuals, 87 (56.5%) showed the typical 15q11-q13 deletion subtypes, 62 (40.3%) showed non-deletion maternal disomy 15 and five individuals (3.2%) had separate unexpected microarray findings. For example, one PWS male had Klinefelter syndrome with segmental isodisomy identified in both chromosomes 15 and X. Thirty-five (40.2%) of 87 individuals showed typical larger 15q11-q13 Type I deletion and 52 individuals (59.8%) showed typical smaller Type II deletion. Twenty-four (38.7%) of 62 PWS individuals showed microarray patterns indicating either maternal heterodisomy 15 subclass or a rare non-deletion (epimutation) imprinting center defect. Segmental isodisomy 15 was seen in 34 PWS subjects (54.8%) with 15q26.3, 15q14 and 15q26.1 bands most commonly involved and total isodisomy 15 seen in four individuals (6.5%). In summary, we report on PWS participants consecutively enrolled internationally in a single clinical trial with high-resolution chromosome microarray analysis to determine and describe an unbiased estimate of the frequencies and types of genetic defects and address potential at-risk genetic disorders in those with maternal disomy 15 subclasses in the largest PWS cohort studied to date. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers–Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. [ABSTRACT FROM AUTHOR]

Ehlers-Danlos syndromes (EDS) are a genetically heterogeneous group of inherited connective tissue disorders classified into six major types with a variable collection of findings and different inheritance patterns. Although complications occur in about one-half of pregnancies in women with EDS, the majority can have a good outcome if managed appropriately. Classic EDS is characterized by joint hypermobility, loose skin with poor healing and easy bruising, musculoskeletal problems with chronic pain and at risk for pre-term delivery. In addition, the vascular form of EDS can have cardiac anomalies, aneurysms, gastrointestinal perforation and uterine rupture during pregnancy. Due to overlapping features among the connective tissue disorders, it is difficult to categorize the disorder into specific types without detailed genetic testing which is now available through advanced genomic technology using next-generation DNA sequencing, searching genomic databases and bioinformatics approach. Therefore, obstetrical complications are variable but relate to specific connective tissue disorders requiring an exact diagnosis. There are several dozen genes causing connective tissue disorders that are currently available for testing using next-generation sequencing and bioinformatics to provide pertinent care, treatment and surveillance of the affected pregnant woman but also for her at-risk fetus related to the specific heritable condition. [ABSTRACT FROM AUTHOR]

We report a 20 year follow up on a Caucasian female, now 26 years of age, with Prader-Willi syndrome (PWS) harboring an atypical 15q11-q13 submicroscopic deletion of 100–200 kb in size first detected in 1996 involving the imprinting center, SNRPN gene and surrounding region. PWS is a rare complex disorder caused by the loss of paternally expressed genes in the 15q11-q13 region. With high resolution chromosomal microarray and methylation – specific MLPA analysis, we updated the genetic findings on our patient and found a 209,819bp deletion including the SNURF-SNRPN gene complex which includes the imprinting center and the SNORD116 region. We compared with four other similarly reported individuals in the literature with atypical submicroscopic deletions within this region but without imprinting center involvement to better characterize the specific genetic lesions causing PWS clinical findings. Clinically, our patient met the diagnostic criteria of PWS including infantile hypotonia, a poor suck with feeding difficulties, global developmental delays and later food foraging, childhood obesity, small hands and skin picking. Small atypical deletions of comparable sizes were seen in the 15q11-q13 region in all five cases and similar behavioral/physical characteristics were found despite an imprinting defect in our patient. These results further support an overlapping critical deletion region involving the non-coding snoRNA SNORD116 in common in the five individuals playing a key role in contributing to the PWS phenotype. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to develop syndrome-specific standardized growth curves for growth hormone–treated Prader-Willi syndrome (PWS) individuals aged 0 to 18 years. Anthropometric growth-related measures were obtained on 171 subjects with PWS who were treated with growth hormone for at least 40% of their lifespan. They had no history of scoliosis. PWS standardized growth curves were developed for 7 percentile ranges using the LMS method for weight, height, head circumference, weight/length, and BMI along with normative 3rd, 50th, and 97th percentiles plotted using control data from the literature and growth databases. Percentiles were plotted on growth charts for comparison purposes. Growth hormone treatment appears to normalize stature and markedly improves weight in PWS compared with standardized curves for non–growth hormone–treated PWS individuals. Growth chart implications and recommended usage are discussed. [ABSTRACT FROM AUTHOR]

Objective To provide an update of currently recognized clinically relevant candidate and known genes for human reproduction and related infertility plotted on high resolution chromosome ideograms (850 band level) and represented alphabetically in tabular form. Method Descriptive authoritative computer-based website and peer-reviewed medical literature searches used pertinent keywords representing human reproduction and related infertility along with genetics and gene mutations. A master list of genes associated with human reproduction and related infertility was generated with a visual representation of gene locations on high resolution chromosome ideograms. GeneAnalytics pathway analysis was carried out on the resulting list of genes to assess underlying genetic architecture for infertility. Results Advances in genetic technology have led to the discovery of genes responsible for reproduction and related infertility. Genes identified (N = 371) in our search primarily impact ovarian steroidogenesis through sex hormone biology, germ cell production, genito-urinary or gonadal development and function, and related peptide production, receptors and regulatory factors. Conclusions The location of gene symbols plotted on high resolution chromosome ideograms forms a conceptualized image of the distribution of human reproduction genes. The updated master list can be used to promote better awareness of genetics of reproduction and related infertility and advance discoveries on genetic causes and disease mechanisms. [ABSTRACT FROM AUTHOR]

We report a 36-year-old Caucasian male identified with distal partial trisomy 15q and partial monosomy 16p from an unbalanced chromosome translocation detected by microarray and FISH analysis. He had a history of developmental delay and intellectual disability, chronic anemia, tall and slender stature, thoracic scoliosis and lumbar lordosis, and dysmorphic features. The distal partial trisomy 15q included the insulin-like growth factor 1 receptor gene involved with growth, while genes in the distal partial monosomy 16p region are involved with alpha hemoglobin production, intellectual disability, dysmorphic features, and acromegaly. The chromosome derivative found in our patient contains genes known to play a role in his phenotype. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families. [ABSTRACT FROM AUTHOR]

Patients with the 15q11.2 BP1-BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1-BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%-1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1-BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. [ABSTRACT FROM AUTHOR]

Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered (e.g., CDH6, FAT2, PCDH8, CTNNA3, ANKRD11). Other genes related to neurogenesis and neuronal migration (e.g., SEMA3F, MIDN), were also identified. [ABSTRACT FROM AUTHOR]

We report our experience with high resolution microarray analysis in infants and young children with developmental disability and/or aberrant behavior enrolled at the Centro Ann Sullivan del Peru in Lima, Peru, a low income country. Buccal cells were collected with cotton swabs from 233 participants for later DNA isolation and identification of copy number variation (deletions/duplications) and regions of homozygosity (ROH) for estimating consanguinity status in 15 infants and young children (12 males, 3 females; mean age ± SD = 28.1 m ± 7.9 m; age range 14 m-41 m) randomly selected for microarray analysis. An adequate DNA yield was found in about one-half of the enrolled participants. Ten participants showed deletions or duplications containing candidate genes reported to impact behavior or cognitive development. Five children had ROHs which could have harbored recessive gene alleles contributing to their clinical presentation. The coefficient of inbreeding was calculated and three participants showed first-second cousin relationships, indicating consanguinity. Our preliminary study showed that DNA isolated from buccal cells using cotton swabs was suboptimal, but yet in a subset of participants the yield was adequate for high resolution microarray analysis and several genes were found that impact development and behavior and ROHs identified to determine consanguinity status. [ABSTRACT FROM AUTHOR]

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader–Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASDs) are neurobehavioral disorders characterized by abnormalities in three behavioral domains including social interaction, impaired communication, and repetitive stereotypic behaviors. ASD affects approximately 1% of children and is on the rise with significant genetic mechanisms underlying these disorders. We review the current understanding of the role of genetic and metabolic factors contributing to ASD with the use of new genetic technology. Fifty percent is diagnosed with chromosomal abnormalities, small DNA deletions/duplications, single-gene conditions, or metabolic disturbances. Genetic evaluation is discussed along with psychiatric treatment and approaches for selection of medication to treat associated challenging behaviors or comorbidities seen in ASD. We emphasize the importance of prioritizing treatment based on target symptom clusters and in what order for individuals with ASD, as the treatment may vary from patient to patient. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To generate and report standardized growth curves for weight, length, head circumference, weight/length, and BMI for non- growth hormone-treated white infants (boys and girls) with Prader- Willi syndrome (PWS) between 0 and 36 months of age. The goal was to monitor growth and compare data with other infants with PWS. METHODS: Anthropométrie measures (W = 758) were obtained according to standard methods and analyzed from 186 non-growth hormone-treated white infants (108 boys and 78 girls) with PWS between 0 and 36 months of age. Standardized growth curves were developed and the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles were calculated by using the LMS (refers to A, jll, and a) smoothing procedure method for weight, length, head circumference, weight/ length, and BMI along with the normative 50th percentile using Centers for Disease Control and Prevention national growth data from 2003. The data were plotted for comparison purposes. RESULTS: Five separate standardized growth curves (weight, length, head circumference, weight/length, and BMI) representing 7 percentile ranges were developed from 186 non-growth hormone-treated white male and female infants with PWS aged 0 to 36 months, and the normative 50th percentile was plotted on each standardized infant growth curve. CONCLUSIONS: We encourage the use of these growth standards when examining infants with PWS and evaluating growth for comparison purposes, monitoring for growth patterns, nutritional assessment, and recording responses to growth hormone therapy, commonly used in infants and children with PWS. [ABSTRACT FROM AUTHOR]

Background: Tetralogy of Fallot (TOF) is the most commonly observed conotruncal congenital heart defect. Treatment of these patients has evolved dramatically in the last few decades, yet a genetic explanation is lacking for the failure of cardiac development for the majority of children with TOF. Our goal was to perform genome wide analyses and characterize expression patterns in cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with tetralogy of Fallot. Methods: We employed genome wide gene expression microarrays to characterize cardiovascular tissue (right ventricle, pulmonary valve and pulmonary artery) obtained at the time of reconstructive surgery from 19 children with TOF (16 idiopathic and three with 22q11.2 deletions) and compared gene expression patterns to normally developing subjects. Results: We detected a signal from approximately 26,000 probes reflecting expression from about half of all genes, ranging from 35% to 49% of array probes in the three tissues. More than 1,000 genes had a 2-fold change in expression in the right ventricle (RV) of children with TOF as compared to the RV from matched control infants. Most of these genes were involved in compensatory functions (e.g., hypertrophy, cardiac fibrosis and cardiac dilation). However, two canonical pathways involved in spatial and temporal cell differentiation (WNT, p = 0.017 and Notch, p = 0.003) appeared to be generally suppressed. Conclusions: The suppression of developmental networks may represent a remnant of a broad malfunction of regulatory pathways leading to inaccurate boundary formation and improper structural development in the embryonic heart. We suggest that small tissue specific genomic and/or epigenetic fluctuations could be cumulative, leading to regulatory network disruption and failure of proper cardiac development. [ABSTRACT FROM AUTHOR]

Mammals inherit two complete sets of chromosomes, one from the father and one from the mother, and most autosomal genes are expressed from both maternal and paternal alleles. Imprinted genes show expression from only one member of the gene pair (allele) and their expression are determined by the parent during production of the gametes. Imprinted genes represent only a small subset of mammalian genes that are present but not imprinted in other vertebrates. Genomic imprints are erased in both germlines and reset accordingly; thus, reversible depending on the parent of origin and leads to differential expression in the course of development. Genomic imprinting has been studied in humans since the early 1980's and accounts for several human disorders. The first report in humans occurred in Prader-Willi syndrome due to a paternal deletion of chromosome 15 or uniparental disomy 15 (both chromosome 15s from only one parent) and similar genetic disturbances were reported later in Angelman syndrome. [ABSTRACT FROM AUTHOR]

Background Prader-Willi syndrome (PWS) is a complex genetic disorder with errors in genomic imprinting, generally due to a paternal deletion of chromosome 15q11-q13 region. Maternal disomy 15 (both 15s from the mother) is the second most common form of PWS resulting from a trisomic zygote followed by trisomy rescue in early pregnancy and loss of the paternal chromosome 15. However, trisomy 15 or mosaicism for trisomy 15 may be present in the placenta possibly leading to placental abnormalities affecting gestational age and delivery. Methods and Subjects We examined growth and gestational data from 167 PWS infants (93 males and 74 females; 105 infants with 15q11-q13 deletion and 62 infants with maternal disomy 15) to determine if there are differences in gestation between the two genetic subtypes. Results No significant differences in growth data (birth weight, length, head circumference) or average gestational ages were found between the two genetic subgroups. However, post-term deliveries (> 42 weeks gestation) were more common in the maternal disomy group (i.e., 12 of 62 infants) compared with the deletion group (i.e., 7 of 105 infants) (chi-square test=6.22; p<0.02). The distribution of gestational ages in the 15q11-q13 deletion group was more bell-shaped or normal while the distribution in the maternal disomy group suggested a bimodal pattern. Conclusions Maternal disomy 15 in PWS may contribute to disturbances in gestational age and delivery by impacting on placental structure or function secondary to the abnormal chromosomal number in the placental cells or in mechanisms leading to the maternal disomy status in PWS infants. [ABSTRACT FROM AUTHOR]

In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting. [ABSTRACT FROM AUTHOR]

Objective. To determine whether phenotypic differences exist among individuals with Prader-Willi syndrome with either type I or type II deletions of chromosome 15 or maternal disomy 15 leading to a better understanding of cause and pathophysiology of this classical genetic syndrome. Methods. We analyzed clinical, anthropometric, and behavioral data in 12 individuals (5 men, 7 women; mean age: 25.9 ± 8.8 years) with PWS and a type I (TI) deletion, 14 individuals (6 men, 8 women; mean age: 19.6 ± 6.5 years) with PWS and a type II (TII) deletion, and 21 individuals (10 men, 11 women; mean age: 23.6 ± 9.2 years) with PWS and maternal disomy 15 (UPD). The deletion type was determined by genotyping of DNA markers between proximal chromosome 15 breakpoints BP1 and BP2. TI deletions are ∼500 kb larger than TII deletions. Several validated psychological and behavioral tests were used to assess phenotypic characteristics of individuals with PWS representing the 3 genetic sub-types. Results. Significant differences were found between the 2 deletion groups and those with UPD in multiple psychological and behavorial tests, but no differences were observed in other clinical or anthropometric data studied. Adaptive behavior scores were generally worse in individuals with PWS and the TI deletion, and specific obsessive-compulsive behaviors were more evident in the TI individuals compared with those with UPD. Individuals with PWS with TI deletions also had poorer reading and math skills as well as visual-motor integration. Conclusions. Our study indicates that individuals with TI deletion generally have more behavioral and psychological problems than individuals with the TII deletion or UPD. Four recently identified genes have been identified in the chromosome region between BP1 and BP2 with 1 of the genes (NIPA-1) expressed in mouse brain tissue but not thought to be imprinted. It may be important for brain development. [ABSTRACT FROM AUTHOR]

33114160 15 Forster J., Duis J., Butler M.G. Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome. Furthermore, early diagnosis of PWS may reduce obesity and associated comorbidities. This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader-Willi syndrome (PWS) and their reflective area of interest impacting this rare disorder. Holland et al. [[6]] further defined mental and behavioral disturbances that occur in genetically determined neurodevelopmental syndromes such as PWS and generated a model that brings together diagnostic-psychologic developmental approaches with the aim of matching specific behaviors and their neural mechanisms focused on PWS. [Extracted from the article]

Reviews the behavioral, cognitive, and other psychological features of Prader-Willi syndrome. History and prevalence; Prenatal development; Birth and early infancy; Genetic aspects; Eating disorder; Behavioral and cognitive development; Adolescence and adulthood; Serious behavior problems and psychiatric symptoms; Cognitive characteristics; Academic achievement; Laboratory assessments of learning and memory.

Chromosome breakage analysis with Mitomycin C (MMC) and sister chromatid exchanges (SCE) were obtained on 10 computer operators with computer exposure for a minimum of 3 hours per day for 4 years and 10 control subjects matched for age and personal lifestyle. No difference was found between the two groups in the total number of chromatid and chromosome aberrations in cells grown at 48 and/or 96 hours in Mitomycin C (20 or 50 ng/ml‐final concentration). The average number of SCE per cell in approximately 30 cells from each person was 6.4±1.1 (mean ± standard deviation) for the computer operators and 9.2 ± 1.6 for the controls. This difference was significant (p <.001). The replicative index was significantly higher (p<.01) in computer operators than in control subjects. The number of SCE appeared not to be influenced by the years of computer exposure. Additional studies with larger sample sizes will be needed to identify if significant differences exist in cell kinetics and sister chromatid exchanges in individuals employed as computer operators. [ABSTRACT FROM PUBLISHER]

Details a study which examined cytogenetic records from consecutive nononcology blood specimens from 2,821 patients who were referred for cytogenetic services to Vanderbilt University from January 1985 to December 1992; The most common reasons for referral; Information on fragile X syndrome, multiple abortions, chromosomal abnormalities, Down syndrome, Turner syndrome and more.

Abstract. Standards (95th, 50th, and 5th percentiles) in fragile X syndrome for weight, height, head circumference, ear length, and testicular volume are reported. For comparison with fragile X syndrome standardized curves, normal control data from the literature were similarly plotted and curves produced. These standards reflect the physical parameters that are frequently abnormal in males with the fragile X syndrome and should be useful in the medical management of patients with this syndrome. The standards may also be used to help identify those individuals, particularly the younger males, for chromosome studies to confirm the clinical impression of the fragile X syndrome. [ABSTRACT FROM AUTHOR]

Abstract. We report standards (95th, 50th, and 5th centiles) in Prader-Willi syndrome for weight, height, sitting height, head circumference, head length, head breadth, hand length, middle finger length, palm length, hand breadth, foot length, foot breadth, triceps skinfold, and subscapular skinfold. For comparison with Prader-Willi syndrome standardized curves, normal control data from the literature were plotted similarly and standard curves were produced. We encourage the use of these standards with the examination of patients who have Prader-Willi syndrome and in the comparison of the patient who has Prader-Willi syndrome with other similarly affected individuals. The standards may also be useful for assisting in the diagnosis of Prader-Willi syndrome, particularly in younger individuals. [ABSTRACT FROM AUTHOR]

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings. [ABSTRACT FROM AUTHOR]

Human genetic studies have implicated more than a hundred genes in Autism Spectrum Disorder (ASD). Understanding how variation in implicated genes influence expression of co-occurring conditions and drug response can inform more effective, personalized approaches for treatment of individuals with ASD. Rapidly translating this information into the clinic requires efficient algorithms to sort through the myriad of genes implicated by rare gene-damaging single nucleotide and copy number variants, and common variation detected in genome-wide association studies (GWAS). To pinpoint genes that are more likely to have clinically relevant variants, we developed a functional annotation pipeline. We defined clinical relevance in this project as any ASD associated gene with evidence indicating a patient may have a complex, co-occurring condition that requires direct intervention (e.g., sleep and gastrointestinal disturbances, attention deficit hyperactivity, anxiety, seizures, depression), or is relevant to drug development and/or approaches to maximizing efficacy and minimizing adverse events (i.e., pharmacogenomics). Starting with a list of all candidate genes implicated in all manifestations of ASD (i.e., idiopathic and syndromic), this pipeline uses databases that represent multiple lines of evidence to identify genes: (1) expressed in the human brain, (2) involved in ASD-relevant biological processes and resulting in analogous phenotypes in mice, (3) whose products are targeted by approved pharmaceutical compounds or possessing pharmacogenetic variation and (4) whose products directly interact with those of genes with variants recommended to be tested for by the American College of Medical Genetics (ACMG). Compared with 1000 gene sets, each with a random selection of human protein coding genes, more genes in the ASD set were annotated for each category evaluated (p ≤ 1.99 × 10−2). Of the 956 ASD-implicated genes in the full set, 18 were flagged based on evidence in all categories. Fewer genes from randomly drawn sets were annotated in all categories (x = 8.02, sd = 2.56, p = 7.75 × 10−4). Notably, none of the prioritized genes are represented among the 59 genes compiled by the ACMG, and 78% had a pathogenic or likely pathogenic variant in ClinVar. Results from this work should rapidly prioritize potentially actionable results from genetic studies and, in turn, inform future work toward clinical decision support for personalized care based on genetic testing. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) consists of a genetically heterogenous group of neurobehavioral disorders characterized by impairment in three behavioral domains including communication, social interaction, and stereotypic repetitive behaviors. ASD affects more than 1% of children in Western societies, with diagnoses on the rise due to improved recognition, screening, clinical assessment, and diagnostic testing. We reviewed the role of genetic and metabolic factors which contribute to the causation of ASD with the use of new genetic technology. Up to 40 percent of individuals with ASD are now diagnosed with genetic syndromes or have chromosomal abnormalities including small DNA deletions or duplications, single gene conditions, or gene variants and metabolic disturbances with mitochondrial dysfunction. Although the heritability estimate for ASD is between 70 and 90%, there is a lower molecular diagnostic yield than anticipated. A likely explanation may relate to multifactorial causation with etiological heterogeneity and hundreds of genes involved with a complex interplay between inheritance and environmental factors influenced by epigenetics and capabilities to identify causative genes and their variants for ASD. Behavioral and psychiatric correlates, diagnosis and genetic evaluation with testing are discussed along with psychiatric treatment approaches and pharmacogenetics for selection of medication to treat challenging behaviors or comorbidities commonly seen in ASD. We emphasize prioritizing treatment based on targeted symptoms for individuals with ASD, as treatment will vary from patient to patient based on diagnosis, comorbidities, causation, and symptom severity. [ABSTRACT FROM AUTHOR]

The 15q11.2 BP1-BP2 microdeletion (Burnside–Butler) syndrome is emerging as the most frequent pathogenic copy number variation (CNV) in humans associated with neurodevelopmental disorders with changes in brain morphology, behavior, and cognition. In this study, we explored functions and interactions of the four protein-coding genes in this region, namely NIPA1, NIPA2, CYFIP1, and TUBGCP5, and elucidate their role, in solo and in concert, in the causation of neurodevelopmental disorders. First, we investigated the STRING protein-protein interactions encompassing all four genes and ascertained their predicted Gene Ontology (GO) functions, such as biological processes involved in their interactions, pathways and molecular functions. These include magnesium ion transport molecular function, regulation of axonogenesis and axon extension, regulation and production of bone morphogenetic protein and regulation of cellular growth and development. We gathered a list of significantly associated cardinal maladies for each gene from searchable genomic disease websites, namely MalaCards.org: HGMD, OMIM, ClinVar, GTR, Orphanet, DISEASES, Novoseek, and GeneCards.org. Through tabulations of such disease data, we ascertained the cardinal disease association of each gene, as well as their expanded putative disease associations. This enabled further tabulation of disease data to ascertain the role of each gene in the top ten overlapping significant neurodevelopmental disorders among the disease association data sets: (1) Prader–Willi Syndrome (PWS); (2) Angelman Syndrome (AS); (3) 15q11.2 Deletion Syndrome with Attention Deficit Hyperactive Disorder & Learning Disability; (4) Autism Spectrum Disorder (ASD); (5) Schizophrenia; (6) Epilepsy; (7) Down Syndrome; (8) Microcephaly; (9) Developmental Disorder, and (10) Peripheral Nervous System Disease. The cardinal disease associations for each of the four contiguous 15q11.2 BP1-BP2 genes are NIPA1- Spastic Paraplegia 6; NIPA2—Angelman Syndrome and Prader–Willi Syndrome; CYFIP1—Fragile X Syndrome and Autism; TUBGCP5—Prader–Willi Syndrome. The four genes are individually associated with PWS, ASD, schizophrenia, epilepsy, and Down syndrome. Except for TUBGCP5, the other three genes are associated with AS. Unlike the other genes, TUBGCP5 is also not associated with attention deficit hyperactivity disorder and learning disability, developmental disorder, or peripheral nervous system disease. CYFIP1 was the only gene not associated with microcephaly but was the only gene associated with developmental disorders. Collectively, all four genes were associated with up to three-fourths of the ten overlapping neurodevelopmental disorders and are deleted in this most prevalent known pathogenic copy number variation now recognized among humans with these clinical findings. [ABSTRACT FROM AUTHOR]

Prader–Willi syndrome (PWS) is recognized as the first example of genomic imprinting, generally due to a de novo paternal 15q11-q13 deletion. PWS is considered the most common genetic cause of marked obesity in humans. Scoliosis, kyphosis, and kyphoscoliosis are commonly seen in children and adolescents with PWS with a prevalence of spinal deformities cited between 15% to 86%. Childhood risk is 70% or higher, until skeletal maturity, with a bimodal age distribution with one peak before 4 years of age and the other nearing adolescence. As few reports are available on treating scoliosis in PWS, we described clinical observations, risk factors, therapeutic approaches and opinions regarding orthopedic care based on 20 years of clinical experience. Treatments include diligent radiographic screening, starting once a child can sit independently, ongoing physical therapy, and options for spine casting, bracing and surgery, depending on the size of the curve, and the child's age. Similarly, there are different surgical choices including a spinal fusion at or near skeletal maturity, versus a construct that allows continued growth while controlling the curve for younger patients. A clear understanding of the risks involved in surgically treating children with PWS is important and will be discussed. [ABSTRACT FROM AUTHOR]

Prader–Willi syndrome (PWS) is a complex genetic disorder with three genetic classes. Patients with PWS are characterized by severe hypotonia, developmental delay, behavioral problems, learning disabilities and morbid obesity in early childhood if untreated. Data were collected through Rare Disease Clinical Research Network (RDCRN) from four study centers which evaluated patients with PWS. The Behavior Assessment System for Children 2nd edition (BASC-2) was chosen to provide behavioral assessment. Data from 330 participants ((64% 15q11-q13 deletion (DEL), 36% maternal disomy 15 (UPD)) were separated into three age groups and analyzed, 68% of whom were still actively receiving recombinant human growth hormone (rhGH) treatment. When comparing the BASC results by molecular subtype, parent-reported aggression was higher for the deletion than for the UPD cohort (p = 0.007). Participants who were on rhGH treatment showed lower scores for parent-reported hyperactivity and aggression (p = 0.04, 0.04, respectively), and a trend for anger control (p = 0.06) and teacher-reported attention problems and aggression (p = 0.01, 0.004, respectively). Additional adjusted analyses were undertaken and significant differences were noted in the GH versus non-GH treated groups for only teacher-reported aggression, which increased in the No GH treated patient group (p = 0.03). This study showed documented differences in PWS behavior by molecular class and rhGH treatment. RhGH therapy may be beneficial for certain behaviors in patients with PWS; however, observed differences need more studies for confirmation in the future. [ABSTRACT FROM AUTHOR]

Prader–Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2–q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or blood clots and venous thromboembolism (VTE) are uncommon but reported in PWS. Two phases of analyses were conducted in our study: unadjusted and adjusted frequency with odds ratios and a regression analysis of risk factors. Individuals with PWS or non-PWS controls with exogenous obesity were identified by specific International Classification of Diseases (ICD)-9 diagnostic codes reported on more than one occasion to confirm the diagnosis of PWS or exogenous obesity in available national health claims insurance datasets. The overall average age or average age per age interval (0–17 year, 18–64 year, and 65 year+) and gender distribution in each population were similar in 3136 patients with PWS and 3945 non-PWS controls for comparison purposes, with exogenous obesity identified from two insurance health claims dataset sources (i.e., commercial and Medicare advantage or Medicaid). For example, 65.1% of the 3136 patients with PWS were less than 18 years old (subadults), 33.2% were 18–64 years old (adults), and 1.7% were 65 years or older. After adjusting for comorbidities that were identified with diagnostic codes, we found that commercially insured PWS individuals across all age cohorts were 2.55 times more likely to experience pulmonary embolism (PE) or deep vein thrombosis (DVT) than for obese controls (p-value: 0.013; confidence interval (CI): 1.22–5.32). Medicaid-insured individuals across all age cohorts with PWS were 0.85 times more likely to experience PE or DVT than obese controls (p-value: 0.60; CI: 0.46–1.56), with no indicated age difference. Age and gender were statistically significant predictors of VTEs, and they were independent of insurance coverage. There was an increase in occurrence of thrombotic events across all age cohorts within the PWS patient population when compared with their obese counterparts, regardless of insurance type. [ABSTRACT FROM AUTHOR]

The 15q11.2 BP1–BP2 microdeletion (Burnside–Butler) syndrome is an emerging disorder that encompasses four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5). When disturbed, these four genes can lead to cognitive impairment, language and/or motor delay, psychiatric/behavioral problems (attention-deficit hyperactivity, autism, dyslexia, schizophrenia/paranoid psychosis), ataxia, seizures, poor coordination, congenital anomalies, and abnormal brain imaging. This microdeletion was reported as the most common cytogenetic finding when using ultra-high- resolution chromosomal microarrays in patients presenting for genetic services due to autism with or without additional clinical features. Additionally, those individuals with Prader–Willi or Angelman syndromes having the larger typical 15q11–q13 type I deletion which includes the 15q11.2 BP1–BP2 region containing the four genes, show higher clinical severity than those having the smaller 15q11–q13 deletion where these four genes are intact. Two of the four genes (i.e., NIPA1 and NIPA2) are expressed in the brain and encode magnesium transporters. Magnesium is required in over 300 enzyme systems that are critical for multiple cellular functions, energy expenditure, protein synthesis, DNA transcription, and muscle and nerve function. Low levels of magnesium are found in those with seizures, depression, and acute or chronic brain diseases. Anecdotally, parents have administered magnesium supplements to their children with the 15q11.2 BP1–BP2 microdeletion and have observed improvement in behavior and clinical presentation. These observations require more attention from the medical community and should include controlled studies to determine if magnesium supplements could be a treatment option for this microdeletion syndrome and also for a subset of individuals with Prader–Willi and Angelman syndromes. [ABSTRACT FROM AUTHOR]

Prader‐Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low‐anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair‐haired (p < 0.001). Participants in both genetic groups receiving GH were taller (p = 0.005), had larger HCs (p = 0.005), and longer hands (p = 0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose, and genitalia. [ABSTRACT FROM AUTHOR]

Mowat–Wilson syndrome (MWS) is a rare genetic neurodevelopmental congenital disorder associated with various defects of the zinc finger E-box binding homeobox 2 (ZEB2) gene. The ZEB2 gene is autosomal dominant and encodes six protein domains including the SMAD-binding protein, which functions as a transcriptional corepressor involved in the conversion of neuroepithelial cells in early brain development and as a mediator of trophoblast differentiation. This review summarizes reported ZEB2 gene variants, their types, and frequencies among the 10 exons of ZEB2. Additionally, we summarized their corresponding encoded protein defects including the most common variant, c.2083 C>T in exon 8, which directly impacts the homeodomain (HD) protein domain. This single defect was found in 11% of the 298 reported patients with MWS. This review demonstrates that exon 8 encodes at least three of the six protein domains and accounts for 66% (198/298) of the variants identified. More than 90% of the defects were due to nonsense or frameshift changes. We show examples of protein modeling changes that occurred as a result of ZEB2 gene defects. We also report a novel pathogenic variant in exon 8 in a 5-year-old female proband with MWS. This review further explores other genes predicted to be interacting with the ZEB2 gene and their predicted gene–gene molecular interactions with protein binding effects on embryonic multi-system development such as craniofacial, spine, brain, kidney, cardiovascular, and hematopoiesis. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is a chronic debilitating neuropsychiatric disorder with multiple risk factors involving numerous complex genetic influences. We examined and updated a master list of clinically relevant and susceptibility genes associated with SCZ reported in the literature and genomic databases dedicated to gene discovery for characterization of SCZ genes. We used the commercially available GeneAnalytics computer-based gene analysis program and integrated genomic databases to create a molecular profile of the updated list of 608 SCZ genes to model their impact in select categories (tissues and cells, diseases, pathways, biological processes, molecular functions, phenotypes and compounds) using specialized GeneAnalytics algorithms. Genes for schizophrenia were predominantly expressed in the cerebellum, cerebral cortex, medulla oblongata, thalamus and hypothalamus. Psychiatric/behavioral disorders incorporating SCZ genes included ADHD, bipolar disorder, autism spectrum disorder and alcohol dependence as well as cancer, Alzheimer's and Parkinson's disease, sleep disturbances and inflammation. Function based analysis of major biological pathways and mechanisms associated with SCZ genes identified glutaminergic receptors (e.g., GRIA1 , GRIN2 , GRIK4 , GRM5 ), serotonergic receptors (e.g., HTR2A , HTR2C ), GABAergic receptors (e.g., GABRA1, GABRB2), dopaminergic receptors (e.g., DRD1 , DRD2 ), calcium-related channels (e.g., CACNA1H , CACNA1B ), solute transporters (e.g., SLC1A1 , SLC6A2 ) and for neurodevelopment (e.g., ADCY1 , MEF2C , NOTCH2 , SHANK3 ). Biological mechanisms involving synaptic transmission, regulation of membrane potential and transmembrane ion transport were identified as leading molecular functions associated with SCZ genes. Our approach to interrogate SCZ genes and their interactions at various levels has increased our knowledge and insight into the disease process possibly opening new avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Deletions of different regions of chromosome 22q11 have been extensively characterized in the literature, with a recent review outlining common deletions with a standardized system proposed for classification and nomenclature. The genotype-phenotype relationships have not been sufficiently elucidated for these deletions, and it remains unclear which specific genes play the dominant roles in producing associated clinical features. Several deletions involve entirely distinct regions of chromosome 22q11 but do not overlap, suggesting that a number of different genes contribute to the clinical features. Studies of patients with small deletions involving only 1 or 2 genes may provide more convincing evidence for the impact of individual genes on the observed phenotype. In this case report, we present a 12-year-old female with autism, cognitive impairment, dysmorphic features, and behavioral concerns and a 268-kb deletion of chromosome 22q11.22 including TOP3B, the only recognized disease-causing gene in the deletion. The mechanism of pathogenesis contributing significantly to our patient's clinical findings may relate to interaction between TOP3B and fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates translation and is altered in fragile X syndrome, a condition involving developmental delay, learning disability, and autism. All these features are recognized in our patient. [ABSTRACT FROM AUTHOR]

Objectives To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. Methods We compared amino acids, fatty acids and acylcarni-tines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, pep-tide YY and markers of insulin sensitivity (adiponectin and HOMA-IR). Results Compared with obese controls (OC), children with PWS had fasting hyperghrelinaemia, hyperadiponectinaemia, hypoinsulinaemia and increased ghrelin/PYY. Hyperghrelinaemia, hyperadiponectinaemia and hypoinsulinaemia were more striking in PWS females than males, and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; fasting ghrelin, PYY and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC. Conclusions BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinaemia and hyperphagia, while hyperadiponectinaemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect fasting ghrelin or PYY. [ABSTRACT FROM AUTHOR]

Objective Alcoholism arises from combined effects of multiple biological factors including genetic and non-genetic causes with gene/environmental interaction. Intensive research and advanced genetic technology has generated a long list of genes and biomarkers involved in alcoholism neuropathology. These markers reflect complex overlapping and competing effects of possibly hundreds of genes which impact brain structure, function, biochemical alcohol processing, sensitivity and risk for dependence. Method We compiled a tabular list of clinically relevant genetic biomarkers for alcoholism targeting expression disturbances in the human brain through an extensive search of keywords related to alcoholism, alcohol abuse, and genetics from peer reviewed medical research articles and related nationally sponsored websites. Gene symbols were then placed on high resolution human chromosome ideograms with gene descriptions in tabular form. Results We identified 337 clinically relevant genetic biomarkers and candidate genes for alcoholism and alcohol-responsiveness from human brain research. Genetic biomarkers included neurotransmitter pathways associated with brain reward processes for dopaminergic (e.g., DRD2 , MAOA , and COMT ), serotoninergic (e.g., HTR3A , HTR1B , HTR3B , and SLC6A4 ), GABAergic (e.g., GABRA1 , GABRA2 , and GABRG1 ), glutaminergic ( GAD1 , GRIK3 , and GRIN2C ) and opioid (e.g., OPRM1 , OPRD1 , and OPRK1 ) pathways which presumably impact reinforcing properties of alcohol. Gene level disturbances in cellular and molecular networks impacted by alcohol and alcoholism pathology include transketolase (TKT), transferrin (TF), and myelin (e.g., MBP, MOBP, and MOG). Conclusions High resolution chromosome ideograms provide investigators, physicians, geneticists and counselors a convenient visual image of the distribution of alcoholism genetic biomarkers from brain research with alphabetical listing of genes in tabular form allowing comparison between alcoholism-related phenotypes, and clinically-relevant alcoholism gene(s) at the chromosome band level to guide research, diagnosis, and treatment. Chromosome ideograms may facilitate gene-based personalized counseling of alcohol dependent individuals and their families. [ABSTRACT FROM AUTHOR]

Background: Heritable connective tissue disorders (HCTDs) consist of heterogeneous syndromes. The diagnosis of HCTDs is aided by genomic biotechnologies (e.g., next-generation sequencing panels) facilitating the discovery of novel variants causing disease. Methods: Detailed clinical exam data and CLIA-approved genetic testing results from next generation sequencing of 74 genes known to play a role in HCTDs were manually reviewed and analyzed in one hundred consecutive, unrelated patients with phenotypic features indicative of a HCTD referred over a 3.5-year period (2016–2020) to a specialized academic genetics clinic. The prevalence of symptoms was evaluated in the context of genetic variants. We also determined if symptoms among different organ systems were related and performed latent class analysis to identify distinct groups of patients based on symptomatology. Results: In the cohort of 100 consecutive, unrelated individuals there were four pathogenic, six likely pathogenic and 35 classified potentially pathogenic variants of unknown clinical significance. Patients with potentially pathogenic variants exhibited similar symptom profiles when compared to patients with pathogenic/likely pathogenic variants in the same genes. Although results did not meet a multiple testing corrected threshold, patients with connective tissue symptoms had suggestive evidence of increased odds of having skin (odds ratio 2.18, 95% confidence interval 1.12 to 4.24) and eye symptoms (odds ratio 1.89, 95% confidence interval 0.98 to 3.66) requiring further studies. The best performing latent class analysis results were identified when dividing the dataset into three distinct groups based on age, gender and presence or absence of symptoms in the skeletal, connective tissue, nervous, gastrointestinal and cardiovascular systems. These distinct classes of patients included individuals with: (1) minimal skeletal symptoms, (2) more skeletal but fewer connective tissue, nervous or gastrointestinal symptoms and (3) more nervous system symptoms. Conclusions: We used novel approaches to characterize phenotype-genotype relationships, including pinpointing potentially pathogenic variants, and detecting unique symptom profiles in patients with features of HCTDs. This study may guide future diagnosis and disease/organ system monitoring with continued improvement and surveillance by clinicians for patients and their families. [ABSTRACT FROM AUTHOR]

Despite the well-established burden of illness and the social costs of PWS, the only medication that has been approved by the Food and Drug Administration (FDA) for the management of this disorder is recombinant human growth hormone (rhGH), which was approved in 2000 [[7]]. The Arduous Path to Drug Approval for the Management of Prader-Willi Syndrome: A Historical Perspective and Call to Action Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [[1]]. [Extracted from the article]

Abstract: About 25% of X-linked genes may escape inactivation at least to some degree. However, in vitro results from somatic cell hybrids may not reflect what happens in vivo. Therefore, we analyzed the female/male (F/M) gene fold expression ratio for 299 X-linked and 7795 autosomal genes from 11 different tissues from an existing in vivo microarray database. On average 5.1 and 4.9% of genes showed higher expression in females compared with 7.4 and 7.9% in males, respectively, for X-linked and autosomal genes. A trend was found for F/M gene fold ratios greater than 1.5 for several X-linked genes indicating overexpression in females among multiple tissues. Nine X-linked genes showed overexpression in females in at least 3 of the 11 studied tissues. Of the 9 genes, 6 were located on the short arm and 3 on the long arm of the X chromosome. Six of the 9 genes have previously been reported to escape X inactivation. However, in general, no consistent pattern was seen for the expression of X-linked genes between in vitro and in vivo systems. This study indicates that factors other than the X-inactivation process may impact on the expression of X-linked genes resulting in an overall similar gender expression for both X-linked and autosomal genes. [Copyright &y& Elsevier]