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1.  Clinical Presentation and Microarray Analysis of Peruvian Children with Atypical Development and/or Aberrant Behavior 
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.
doi:10.1155/2014/408516
PMCID: PMC4221906  PMID: 25400949
2.  Assessment and Treatment in Autism Spectrum Disorders: A Focus on Genetics and Psychiatry 
Autism Research and Treatment  2012;2012:242537.
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.
doi:10.1155/2012/242537
PMCID: PMC3420490  PMID: 22934170
3.  Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader–Willi and Alström syndromes 
Advances in genomics and genetics  2015;2015(5):53-75.
Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader–Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.
doi:10.2147/AGG.S74598
PMCID: PMC4334166
hyperphagia; microarray analysis; gene; obesity; exon expression; miRNA expression
4.  FASTING PLASMA LIPID, GLUCOSE, AND INSULIN LEVELS IN PRADER-WILLI SYNDROME AND OBESE INDIVIDUALS 
Plasma lipid, glucose, and insulin levels were measured from 26 patients with Prader-Willi syndrome (16 with the chromosome 15q deletion and 10 with normal chromosomes) and 32 obese, normal individuals. The average percentage of ideal body weight (IBW) for the former group was 175.6 ± 68.0, compared to 150.3 ± 43.8 for the latter. Fasting plasma lipid, glucose, and insulin levels were not significantly different between the two groups. No significant correlations were found among the three measurements in patients with PWS (deletion or nondeletion) or obese individuals and either age or percentage of IBW. Both insulin and glucose levels were higher in the PWS group, while only insulin levels were higher in the obese group compared with normative laboratory standards. Our study supports previously reported lipid, glucose, and insulin data in PWS and obesity.
PMCID: PMC4258708  PMID: 25505362
glucose; insulin; lipids; obesity
5.  AMINO ACID LEVELS IN PRADER-WILLI SYNDROME AND OBESE INDIVIDUALS 
To determine if certain features (e.g., hypopigmentation) seen in persons with Prader-Willi syndrome (PWS) may be reflected in abnormalities of amino acid metabolism, fasting plasma amino acid levels were measured from 25 patients and compared with those in 17 obese individuals. Thirteen of the patients with PWS were previously identified by high-resolution analysis to have chromosome 15q deletion, while 12 had normal chromosomes. Compared with reference plasma levels, several amino acid levels were elevated in both patients and obese individuals. Aspartic acid, taurine, and glutamic acid levels were elevated (>2 Z score) in 44% of the patients with PWS but were increased in only one obese individual. The average phenylalanine and tyrosine levels were not different in the two groups. Significant differences in taurine, cystine, glutamic acid, citrulline, and aspartic acid levels were found. There was no correlation with age, degree of obesity (percentage of ideal body weight), and the degree of elevation of amino acids in either patients with PWS or obese individuals. Similarly, the degree of obesity in those with PWS was not associated with chromosome status. Several amino acid concentrations were abnormal in patients compared with our laboratory reference ranges, but many of these abnormalities were also present in obese individuals. Whether the amino acid changes simply reflect the altered eating habits of obese individuals or whether the altered profile may play a role in appetite or energy regulation is not known.
PMCID: PMC4258711  PMID: 25505361
chromosome 15 deletion; exogenous obesity; hypopigmentation; amino acid
6.  NORMATIVE STANDARDS AND PATTERNING OF FAT AND MUSCLE IN WHITE AND BLACK NEWBORN INFANTS 
Due to the lack of normative data in newborns, we report fat and muscle patterning, and standards for the sums of fat and muscle areas and muscle circumferences for arm, forearm, thigh, and calf in white and black newborn infants that may have clinical application in the assessment of body composition in newborns. Significant differences were found between white males and white females in fatness patterning: white female newborns were larger for all 21 variables except height. Statistically significant differences (t test; p < 0.05) existed for five skinfold measurements (forearm, subscapular, suprailiac, thigh, medial calf), three limb fat areas (forearm, thigh, calf), and the sums of the skinfolds and fat areas despite similar limb circumferences. Black female newborns were larger than black males for five of the eight skinfolds (with a significant difference observed in medial calf skinfold), for all of the limb fat areas, and for the sums of the skinfolds and fat areas. Despite their larger skinfolds and fat areas, black females had smaller circumferences. No sex-related trends or significantly different variables were observed in the muscle patterning of white infants. Differences in muscle patterning were observed between black males and black females, with males having larger values for all 14 variables. Statistically significant differences were found between white and black infants, with white newborns having greater height, medial calf skinfold, and calf fat area.
PMCID: PMC4258714  PMID: 25505363
anthropometry; standardized curves; fatness and muscle patterning; black and white newborn infants
7.  INTRAFAMILIAL AND MIDPARENTAL-CHILD CORRELATIONS AND HERITABILITY ESTIMATES OF ANTHROPOMETRIC MEASUREMENTS IN PRADER-WILLI SYNDROME FAMILIES 
To determine the effects of familial background on anthropometric dimensions in Prader-Willi syndrome (PWS), we measured weight; height; sitting height; longitude and breadth of the head, hands, and feet; head, arm, and calf circumferences; and triceps and subscapular skinfolds in 28 individuals with the syndrome and their natural parents. Midparental-child correlations were significant for height and foot length, with heritability estimates of 0.52 and 0.68, respectively. Significant mother-child correlations were found for weight, height, foot length, and minimal frontal diameter for the total group; in addition, hand length and breadth, and calf and arm circumferences were significant for the patients age 12.5 years or under. These data provide evidence for maternal effects on several physical characteristics in PWS, particularly in younger patients.
PMCID: PMC4259252  PMID: 25505360
anthropometry; familial influences; genetic imprinting; maternal effects
8.  20q13.2-q13.33 deletion syndrome: A case report 
Journal of pediatric genetics  2014;2(3):157-161.
We report a 32-month-old female of Peruvian ethnicity identified with a rare 20q13.2-q13.33 deletion using microarray analysis. She presented with intellectual disability, absent speech, hypotonia, pre- and post-natal growth retardation and an abnormal face with a unilateral cleft lip. Clinical features and genetic findings with the loss of 30 genes, including GNAS, MC3R, CDH4 and TFAP2C, are described in relationship to the very few cases of 20q13 deletion reported in the literature. Deletion of this region may play an important role in neurodevelopment and function and in causing specific craniofacial features.
doi:10.3233/PGE-13065
PMCID: PMC4203459  PMID: 25339993
Microarray analysis; 20q13 deletion; intellectual disability; atypical development; dysmorphic features; cleft lip
9.  Further phenotypic expansion of 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome 
Journal of pediatric genetics  2014;3(1):41-44.
We report a 10-year-old Caucasian male identified with copy number variation detected by microarray analysis including a maternally inherited 15q11.2 microdeletion involving 4 genes, paternally inherited 13q12.2 microdeletion with 10 genes, and a de novo 2q14.3 duplication involving 4 genes. He had a history of speech delay, cognitive deficits, attention deficit hyperactivity disorder and a posterior lenticonus cataract removed at 5 yr of age. The genes on chromosomes 2 and 13 are not known to be involved with cataract formation, which lends further support of the role of the 15q11.2 region and additional evidence for phenotypic expansion of the 15q11.2 BP1-BP2 microdeletion (termed Burnside-Butler) syndrome.
doi:10.3233/PGE-14082
PMCID: PMC4190059  PMID: 25309804
Microarray analysis; motor and language delay; congenital cataracts; dysmorphic features
10.  Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia 
Obesity (Silver Spring, Md.)  2014;22(0 1):S1-S17.
Objective
Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments.
Design and Methods
International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates.
Results
The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified.
Conclusions
This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.
doi:10.1002/oby.20646
PMCID: PMC4159941  PMID: 24574081
11.  Growth Hormone Receptor (GHR) Gene Polymorphism and Prader-Willi Syndrome 
Prader-Willi syndrome (PWS) is a genomic imprinting disorder due to loss of paternally expressed genes in the 15q11-q13 region and characterized by hypotonia, a poor suck, failure to thrive, hypogonadism/hypogenitalism, growth hormone deficiency, learning and behavioral problems and hyperphagia leading to early childhood obesity. Growth hormone acts as a ligand for the growth hormone receptor (GHR) coded by a gene polymorphic for an exon-3 deletion (d3) seen in about 50% of Caucasians and associated with an increased response to growth hormone (GH) therapy. We examined 69 individuals with PWS (average age ± SD = 20.1 ± 12.8y). The GHR allele distribution in our PWS subjects was similar to reported data in the literature with no gender or PWS genetic subtype differences. A negative correlation was found with age for height standard deviational scores and a positive correlation with age for weight and BMI for non-GH treated PWS subjects. Adjusting for effects of age and gender, individuals with PWS and the d3/d3 allele showed a significant increase in BMI compared with those having the full length (fl) allele. In addition, 12 infants and children with PWS were examined when growth and GH data were available before and during GH treatment. A significant increase in growth rate (1.7 times) was noted in the presence of the d3 allele (fl/fl=0.87cm/month; fl/d3 or d3/d3=1.5 cm/month; p < 0.05). The presence of the d3 allele and its impact on growth and medical care of individuals with PWS while on GH therapy should be further investigated.
doi:10.1002/ajmg.a.35980
PMCID: PMC3689873  PMID: 23696513
Growth hormone receptor (GHR); Prader-Willi syndrome; growth hormone treatment; genotype; gene polymorphism
12.  Comparison of biological specimens and DNA collection methods for PCR amplification and microarray analysis 
doi:10.1515/cclm-2012-0429
PMCID: PMC3660108  PMID: 23241593
biological specimens; chromosomal microarray; DNA isolation; genotyping; PCR amplification
13.  Methylation-Specific Multiplex Ligation-Dependent Probe Amplification and Identification of Deletion Genetic Subtypes in Prader-Willi Syndrome 
Purpose: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are complex neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region depending on the parent of origin. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) kits from MRC-Holland (Amsterdam, The Netherlands) were used to detect PWS and AS deletion subtypes. We report our experience with two versions of the MS-MLPA-PWS/AS kit (original A1 and newer B1) in determining methylation status and deletion subtypes in individuals with PWS. Methods: MS-MLPA analysis was performed on DNA isolated from a large cohort of PWS subjects with the MS-MLPA-PWS/AS-A1 and -B1 probe sets. Results: Both MS-MLPA kits will identify deletions in the 15q11-q13 region but the original MS-MLPA-A1 kit has a higher density of probes at the telomeric end of the 15q11-q13 region, which is more useful for identifying individuals with atypical deletions. The newer B1 kit contains more probes in the imprinting center (IC) and adjoining small noncoding RNAs useful in identifying small microdeletions. Conclusion: The A1 kit identified the typical deletions and smaller atypical deletions, whereas the B1 kit was more informative for identifying microdeletions including the IC and SNORD116 regions. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions.
doi:10.1089/gtmb.2011.0115
PMCID: PMC3306590  PMID: 21977908
14.  Growth Standards of Infants With Prader-Willi Syndrome 
Pediatrics  2011;127(4):687-695.
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:
Anthropometric measures (N = 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 λ, μ, and σ) 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.
doi:10.1542/peds.2010-2736
PMCID: PMC3065075  PMID: 21402637
Prader-Willi syndrome; standardized growth curves; obesity; growth hormone therapy
15.  APOA1 gene polymorphisms in the South Asian immigrant population in the United States 
Indian Journal of Human Genetics  2011;17(3):194-200.
BACKGROUND:
Coronary artery disease (CAD) is a leading cause of death in the United States. South Asian immigrants (SAIs) from the Indian subcontinent living in the US are disproportionately at higher risk of CAD than other immigrant populations. Unique genetic factors may predispose SAIs to increased risk of developing CAD when adopting a Western lifestyle including a higher-fat diet, more sedentary behavior and additional gene-environment interactions. SAIs are known to have low levels of the protective high density lipoprotein (HDL) and an altered function for Apo-lipoprotein A-1 (ApoA1), the main protein component of HDL cholesterol. One gene that may be genetically distinctive in this population is APOA1 which codes for ApoA-1 protein, a potentially important contributing factor in the development of CAD.
MATERIALS AND METHODS:
DNA sequencing was performed to determine the status of the seven single-nucleotide polymorphisms (SNPs) in the APOA1 gene from 94 unrelated SAI adults. Genotypes, allelic frequencies, and intragenic linkage disequilibrium of the APOA1 SNPs were calculated.
RESULTS:
Several polymorphisms and patterns were common among persons of south Asian ethnicity. Frequencies for SNPs T655C, T756C and T1001C were found to be different than those reported in European Caucasian individuals. Linkage disequilibrium was found to be present between most (13 of 15) SNP pairings indicating common inheritance patterns.
CONCLUSIONS:
SAIs showed variability in the sequence of the APOA1 gene and linkage disequilibrium for most SNPS. This pattern of APOA1 SNPs may contribute to decreased levels of HDL cholesterol reported in SAIs, leading to an increased risk for developing CAD in this population.
doi:10.4103/0971-6866.92103
PMCID: PMC3276989  PMID: 22345992
APOA1; coronary artery disease; linkage disequilibrium; single nucleotide gene polymorphisms; south Asian immigrants
16.  An Interstitial 15q11-q14 Deletion: Expanded Prader-Willi Syndrome Phenotype 
We present an infant girl with a de novo interstitial deletion of the chromosome 15q11-q14 region, larger than the typical deletion seen in Prader-Willi syndrome (PWS). She presented with features seen in PWS including hypotonia, a poor suck, feeding problems and mild micrognathia. She also presented with features not typically seen in PWS such as preauricular ear tags, a high arched palate, edematous feet, coarctation of the aorta, a PDA and a bicuspid aortic valve. G-banded chromosome analysis showed a large de novo deletion of the proximal long arm of chromosome 15 confirmed using FISH probes (D15511 and GABRB3). Methylation testing was abnormal and consistent with the diagnosis of PWS. Because of the large appearing deletion by karyotype analysis, an array comparative genomic hybridization (CGH) was performed. A 12.3 Mb deletion was found which involved the 15q11-q14 region containing approximately 60 protein coding genes. This rare deletion was approximately twice the size of the typical deletion seen in PWS and involved the proximal breakpoint BP1 and the distal breakpoint was located in the 15q14 band between previously recognized breakpoints BP5 and BP6. The deletion extended slightly distal to the AVEN gene including the neighboring CHRM5 gene. There is no evidence that the genes in the 15q14 band are imprinted; therefore, their potential contribution in this patient's expanded Prader-Willi syndrome phenotype must be a consequence of dosage sensitivity of the genes or due to altered expression of intact neighboring genes from a position effect.
doi:10.1002/ajmg.a.33197
PMCID: PMC2814996  PMID: 20082457
de novo interstitial 15q11-q14 deletion; expanded PWS phenotype; array CGH; genotype-phenotype correlations
17.  A 9-year-old Male with a Duplication of Chromosome 3p25.3p26.2: Clinical Report and Gene Expression Analysis 
We describe a 9-year-old male referred for genetic evaluation for Prader-Willi syndrome (PWS). PWS is the most common genetically-defined cause of life-threatening obesity and results from a functional loss of paternally-expressed genes from the chromosome 15q11-q13 region. The patient presented with pervasive developmental disorder, delayed speech and rapid onset of obesity at age 4 years, all features similar to PWS. However, chromosome 15q11-q13 methylation testing and fragile X studies were normal. GTG-banding and fluorescence in situ hybridization with whole chromosome 3 paint probe and a chromosome 3p subtelomeric probe suggested a duplication of 3p25.3p26.2, a finding supported by comparative genomic hybridization. This region of chromosome 3p contains genes which contribute to obesity and behavioral problems, most notably, ghrelin (GHRL), an oxytocin receptor (OXTR), solute carrier family 6 members (GABA neurotransmitter transporters, SLC6A1 and SLC6A11) and peroxisome proliferator-activated receptor, gamma (PPARG). To characterize these obesity and behavior related genes in our subject, we performed quantitative RT-PCR and compared expression levels with similarly aged male subjects (four nonobese males, four obese males and four PWS males - two with 15q11-q13 deletions and two with maternal disomy 15). Our studies suggest increased expression of several genes in the 3p duplication region, including GHRL and PPARG, which may contribute to the phenotypic features in our 3p duplication subject.
doi:10.1002/ajmg.a.31132
PMCID: PMC2568077  PMID: 16470700
obesity; pervasive developmental disorder; comparative genomic hybridization; gene expression; ghrelin (GHRL); peroxisome proliferator-activated receptor; gamma (PPARG); oxytocin receptor (OXTR); RT-PCR; Prader-Willi syndrome (PWS)
18.  Frequency of Births Due to Assisted Reproductive Technology (ART) in Prader-Willi Syndrome 
Purpose
Prader-Willi syndrome (PWS) is an imprinting disorder characterized by typical facial, physical and cognitive/behavioral features, resulting from lack of paternally-expressed genes on chromosome 15q11.2-q13. Studies have suggested an increased risk of other imprinting disorders in children conceived by assisted reproductive techniques (ART). This study was designed to determine the association between ART and PWS.
Methods
Data on individuals with PWS were collected from three distinct sources and the proportion of ART-births analyzed.
Results
The proportion of ART-births in the Prader-Willi Syndrome Association [PWSA (USA)], Rare Diseases Clinical Research Network (RDCRN), and University of California, Irvine Medical Center (UCIMC) populations was 1.0% (18/1,736), 1.0% (1/98), and 2.0% (1/50), respectively (overall 1.1%; population frequency for the U.S was 1.0%). Interestingly, 2.4% (45/1,898) of participants were co-twins (eleven born after ART procedures); U.S. twin frequency is 1.6% (p=0.007). The proportion of individuals with maternal disomy 15/imprinting defects born after ART was higher than in the total sample, 55.6% (10/18) and 34.5% (431/1,250), respectively.
Conclusion
This study found no association between ART and PWS. There was an increased frequency of twinning. The number of individuals with maternal disomy 15/imprinting defect was nearly double in the ART group compared to the total PWS participants.
doi:10.1038/gim.2013.97
PMCID: PMC4164429  PMID: 23928912
Prader-Willi syndrome; assisted reproductive techniques; imprinting; twinning; RDCRN
19.  Whole Exome Sequencing in Females with Autism Implicates Novel and Candidate Genes 
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.
doi:10.3390/ijms16011312
PMCID: PMC4307305  PMID: 25574603
whole exome sequencing; females; autism spectrum disorder; genetic variants; X chromosome inactivation
20.  DOUBLE-BLIND, RANDOMIZED PLACEBO-CONTROLLED CLINICAL TRIAL OF BENFOTIAMINE FOR SEVERE ALCOHOL DEPENDENCE 
Drug and alcohol dependence  2013;133(2):10.1016/j.drugalcdep.2013.07.035.
Background
Alcohol dependence is associated with severe nutritional and vitamin deficiency. Vitamin B1 (thiamine) deficiency erodes neurological pathways that may influence the ability to drink in moderation. The present study examines tolerability of supplementation using the high-potency thiamine analogue, benfotiamine (BF), and BF’s effects on alcohol consumption in severely affected, self-identified, alcohol dependent subjects.
Methods
A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age=47 years) from the Kansas City area who met DSM-IV-TR criteria current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo (PL) once daily by mouth for 24 weeks with 6 follow-up assessments scheduled at 4 week intervals. Side effects and daily alcohol consumption were recorded.
Results
Seventy (58%) subjects completed 24 weeks of study (N=21 women; N=49 men) with overall completion rates of 55% (N=33) for PL and 63% (N=37) for BF groups. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 BF treated women after 1 month of treatment compared with 2 of 11 on PL. Reductions in total alcohol consumption over 6 months were significantly greater for BF treated women (BF: N=10, −611±380 Std Dev; PL: N=11, −159±562 Std Dev, p-value=0.02).
Conclusions
BF supplementation of actively drinking alcohol dependent men and women was well-tolerated and may discourage alcohol consumption among women. The results do support expanded studies of BF treatment in alcoholism.
doi:10.1016/j.drugalcdep.2013.07.035
PMCID: PMC3818307  PMID: 23992649
Alcoholism; Thiamine; Benfotiamine; Female alcohol consumption
21.  A preliminary case study of androgen receptor gene polymorphism association with impulsivity in women with alcoholism 
Objective
The androgen receptor (AR) gene, located on the X chromosome, contains a common polymorphism involving cytosine–adenine–guanine (CAG) repeats, which impacts disease and could contribute to the unequal sex ratio in alcoholism. CAG repeats in the AR gene are known to correlate with impulsivity in males. We report the first preliminary study examining the association between the number of CAG repeats and measures of impulsivity in females with chronic alcoholism.
Methods
A total of 35 women and 85 men with chronic alcoholism were previously recruited for a nutritional clinical trial, and 26 well-characterized females (19 African–American and seven Caucasian) with alcoholism agreed to participate for genetic testing. Genomic deoxyribonucleic acid (DNA) was isolated from peripheral blood and CAG repeats determined by analyzing polymerase chain reaction (PCR)-amplified products, using the polymorphic AR gene assay. CAG repeat length was correlated with raw scores from the Barratt Impulsivity Scale, version 11 and the Alcoholism Severity Scale.
Results
CAG repeat lengths were significantly longer in Caucasian alcoholic women compared with African–Americans, and the average number of CAG repeats were significantly, positively correlated (P<0.05) with impulsivity scores. Women with average CAG repeat length (CAGave) ≥18, representing the upper quartile of the repeat range, showed significantly greater mean raw impulsivity scores. CAG repeat length appeared to have less effect in African–American compared with Caucasian women, possibly due to a shorter average repeat length.
Conclusion
We found an association between the number of CAG repeats and impulsivity in females with chronic alcoholism, specifically in women with CAGave ≥18, seen more commonly in Caucasian compared with African–American women.
doi:10.2147/AGG.S57771
PMCID: PMC4067054  PMID: 24966714
AR gene; CAG repeat; African-American; Caucasian; behavior
22.  Clinical Report of a 17q12 Microdeletion with Additionally Unreported Clinical Features 
Case Reports in Genetics  2014;2014:264947.
Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tall-appearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified a de novo suspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband's phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient's unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations.
doi:10.1155/2014/264947
PMCID: PMC4060289  PMID: 24991439
23.  X Chromosome Inactivation in Women with Alcoholism 
Background
All female mammals with two X chromosomes balance gene expression with males having only one X by inactivating one of their Xs (X chromosome inactivation, XCI). Analysis of XCI in females offers the opportunity to investigate both X-linked genetic factors and early embryonic development that may contribute to alcoholism. Increases in the prevalence of skewing of XCI in women with alcoholism could implicate biological risk factors.
Methods
The pattern of XCI was examined in DNA isolated in blood from 44 adult females meeting DSM IV criteria for an Alcohol Use Disorder, and 45 control females with no known history of alcohol abuse or dependence. XCI status was determined by analyzing digested and undigested polymerase chain reaction (PCR) products of the polymorphic androgen receptor (AR) gene located on the X chromosome. Subjects were categorized into 3 groups based upon the degree of XCI skewness: random (50:50–64:36), moderately skewed (65:35–80:20) and highly skewed (>80:20).
Results
XCI status from informative females with alcoholism was found to be random in 59% (n=26), moderately skewed in 27% (n=12) or highly skewed in 14% (n=6). Control subjects showed 60%, 29% and 11%, respectively. The distribution of skewed XCI observed among women with alcoholism did not differ statistically from that of control subjects (χ2 =0.14, 2 df, p=0.93).
Conclusions
Our data did not support an increase in XCI skewness among women with alcoholism or implicate early developmental events associated with embryonic cell loss or unequal (non-random) expression of X-linked gene(s) or defects in alcoholism among females.
doi:10.1111/j.1530-0277.2012.01740.x
PMCID: PMC3371305  PMID: 22375556
Alcoholism; Women; X Chromosome Inactivation; Skewness; AR Gene
24.  Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome 
Context:
Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events.
Objective:
The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS.
Evidence:
We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries.
Methodology:
Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN).
Conclusions:
Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.
doi:10.1210/jc.2012-3888
PMCID: PMC3789886  PMID: 23543664
25.  The Neuroanatomy of Genetic Subtype Differences in Prader-Willi Syndrome 
American Journal of Medical Genetics  2012;159B(2):243-253.
Objective
Despite behavioral differences between genetic subtypes of Prader-Willi syndrome, no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)].
Methods
Fifteen individuals with PWS due to a typical deletion ((DEL) Type I; n=5, Type II; n=10), 8 with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume between groups, covarying for age, sex, and body mass index (BMI).
Results
Overall, compared to HWC, PWS individuals had lower gray matter volumes that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower white matter volumes in the brain stem, cerebellum, medial temporal and frontal cortex. Compared to UPD, the DEL subtypes had lower gray matter volume primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and white matter volumes in the orbitofrontal and limbic cortices compared to HWC.
Conclusions
These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.
doi:10.1002/ajmg.b.32022
PMCID: PMC3296480  PMID: 22241551
chromosome 15q; hyperphagia; obesity; voxel-based morphometry; MRI

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