Greenwood Genetics Center

Greenwood, United States

Greenwood Genetics Center

Greenwood, United States

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Fisch G.S.,New York University | Carpenter N.,Center for Genetic Testing | Howard-Peebles P.N.,Genetics and IVF Institute | Holden J.J.A.,Queen's University | And 3 more authors.
American Journal on Intellectual and Developmental Disabilities | Year: 2012

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain-behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers. © EAAIDD.


Sloan J.L.,U.S. National Institutes of Health | Johnston J.J.,U.S. National Institutes of Health | Manoli I.,U.S. National Institutes of Health | Chandler R.J.,U.S. National Institutes of Health | And 22 more authors.
Nature Genetics | Year: 2011

We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in 1/41,000 control individuals, predicting a CMAMMA population incidence of 1/41:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders. © 2011 Nature America, Inc. All rights reserved.


Lindhurst M.J.,U.S. National Institutes of Health | Parker V.E.R.,University of Cambridge | Payne F.,Wellcome Trust Sanger Institute | Sapp J.C.,U.S. National Institutes of Health | And 27 more authors.
Nature Genetics | Year: 2012

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110Î ± catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP 3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. © 2012 Nature America, Inc. All rights reserved.


Fisch G.S.,New York University | Carpenter N.,Center for Genetic Testing | Howard-Peebles P.N.,Genetics and IVF Institute | Holden J.J.A.,Queen's University | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

The course of cognitive-behavioral development in children with intellectual disabilities produced by genetic disorders has only recently begun to be examined systematically. Unfortunately, these studies are few in number. Previously, we examined cognitive-behavioral development in children with the fragile X(FMR1) mutation and found longitudinal decreases in both IQ and adaptive behavior (DQ) scores in most males and females with the full mutation. In this study, we examine longitudinal changes in IQ andDQ in children with neurofibromatosis type 1 (NF1) and Williams-Beuren Syndrome (WBS) by examining differences in composite IQ and DQ scores between the first test (T1) and retest (T2), and compare their developmental trajectory to children with the FMR1 mutation. Sixty-five children with the FMR1 mutation, or NF1, or WBS, ages 4-16 years, were retested two years after initial testing with the Stanford-Binet 4th Edition (SBFE) and the Vineland Adaptive Behavior Scale (VABS). In addition to significant longitudinal declines in IQ and DQnoted previously in children with the FMR1 mutation, we found significant decreases in IQ in males compared to females in the remainder of our sample. We also observed statistically signifi-cant decreases inDQscores among children the FMR1 mutation, as noted previously, but not among children with NF1 or WBS. Moreover, significant declines were found only among males with the FMR1 mutation. Unlike declines in IQ scores, decreases in DQ were not significantly different between males and females. © 2010 Wiley-Liss, Inc.


Motil K.J.,Baylor College of Medicine | Caeg E.,Baylor College of Medicine | Barrish J.O.,Baylor College of Medicine | Geerts S.,University of Alabama at Birmingham | And 8 more authors.
Journal of Pediatric Gastroenterology and Nutrition | Year: 2012

Objective: We conducted a nationwide survey to determine the prevalence of common gastrointestinal and nutritional disorders in Rett syndrome (RTT) based on parental reporting and related the occurrence of these problems to age and methyl-CpG-binding protein 2 (MECP2) gene status. Methods: We designed a questionnaire that probed symptoms, diagnoses, diagnostic tests, and treatment interventions related to gastrointestinal and nutritional problems in RTT. The International Rett Syndrome Foundation distributed the questionnaire to 1666 family-based members and forwarded their responses for our review. We interrogated the Rare Disease Clinical Research Network database to supplement findings related to medications used to treat gastrointestinal problems in RTT. Results: Parents of 983 female patients with RTT (59%) responded and identified symptoms and diagnoses associated with gastrointestinal dysmotility (92%), chewing and swallowing difficulties (81%), weight deficits or excess (47%), growth deficits (45%), low bone mineral content or fractures (37%), and biliary tract disorders (3%). Height-for-age, weight-for-age, and body mass index z scores decreased significantly with age; height-and weight-, but not body mass index-for-age z scores were significantly lower in female subjects with MECP2 mutations than in those without. Vomiting, nighttime awakening, gastroesophageal reflux, chewing difficulty, and choking with feeding were significantly less likely to occur with increasing age. Short stature, low bone mineral content, fractures, and gastrostomy placement were significantly more likely to occur with increasing age. Chewing difficulty, choking with feeding, and nighttime awakening were significantly less likely to occur, whereas short stature was significantly more likely to occur, in female subjects with MECP2 mutations than in those without. Diagnostic evaluations and therapeutic interventions were used less frequently than the occurrence of symptoms or diagnoses in the RTT cohort. Conclusions: Gastrointestinal and nutritional problems perceived by parents are prevalent throughout life in girls and women with RTT and may pose a substantial medical burden for their caregivers. Physician awareness of these features of RTT may improve the health and quality of life of individuals affected with this disorder. © 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.


Hunter A.G.W.,Greenwood Genetics Center | Nezarati M.M.,North York General Hospital | Velsher L.,North York General Hospital
American Journal of Medical Genetics, Part A | Year: 2010

Facial angiofibromas are a major diagnostic sign for tuberous sclerosis (TS) and MEN1, and the former is probably the first disease to be considered by a geneticist when such lesions are found. They occur in up to 90% of persons with TS and 40-80% of individuals with MEN1. Early onset facial angiofibromas that are not associated with any other systemic sign appear to be unusual, and their occurrence can leave the clinician with some uncertainty as to their significance, as well as how to proceed. In this article we describe four patients with what appear to be isolated, bilateral facial angiofibromas. We discuss the significance of these lesions with respect to the conditions in which they have been seen, review prior reports of apparently isolated angiofibromas, and provide some rough calculations as to how likely it would be for an underlying systemic condition to be overlooked after different levels of investigation have been performed. We also look at some aspects of the financial cost/benefit ratio of further investigation of TS beyond a clinical examination. © 2010 Wiley-Liss, Inc.


Peters S.U.,Vanderbilt University | Horowitz L.,Greenwood Genetics Center | Barbieri-Welge R.,Rady Childrens Hospital | Taylor J.L.,Vanderbilt University | Hundley R.J.,Vanderbilt University
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2012

Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a 'syndromic' form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (∼6 Mb) Class I deletions of chromosome 15q11-13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. Methods: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion (∼5 Mb) were enrolled (age range = 2-25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory-seeking behaviors/aversions were given at baseline and after 12 months. Results: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p =.006) and more repetitive behaviors (F = 7.92; p =.008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. Conclusions: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning. © 2011 Association for Child and Adolescent Mental Health.


Ramappa M.,Medical University of South Carolina | Ramappa M.,L v Prasad Eye Institute | Wilson M.E.,Medical University of South Carolina | Rogers R.C.,Greenwood Genetics Center | Trivedi R.H.,Medical University of South Carolina
Journal of AAPOS | Year: 2014

We report a 6-week-old white boy of nonconsanguineous parents who presented with bluish scleral discoloration, thin corneas, and progressive high myopia. A diagnosis of brittle cornea syndrome was confirmed by molecular analysis and prompt measures were taken to manage the condition. Long-term follow-up of children diagnosed with brittle cornea syndrome is important to minimize the risks of corneal rupture and for detecting late-onset systemic conditions. Copyright © 2014 by the American Association for Pediatric Ophthalmology and Strabismus.


Hunter A.G.,Greenwood Genetics Center
American Journal of Medical Genetics, Part A | Year: 2010

The recent series of articles describing human surface anatomy included an article on the ear by Hunter et al. [Hunter et al. (2009); Am J Med Genet Part A 149A: 40-60]. That publication did not include the incisura. This article provides an approach to assessing the incisura in the hope that others may find it useful and/or modify it as appropriate. © 2010 Wiley-Liss, Inc.


Sadler T.W.,Greenwood Genetics Center | Sadler T.W.,University of Utah
American Journal of Medical Genetics, Part A | Year: 2015

To date the etiology of the association called VACTERL remains a mystery. Interestingly, clues as to the origin of this collection of defects may reside in an old hypothesis concerning the midline as a developmental field as postulated by Dr. John Opitz. This theory suggested that the midline was not a separate entity, but could be influenced by other developmental signals. With new information concerning the origin of the left-right axis (laterality) and the importance of communications between this axis and the cranio-caudal (anterior-posterior) axis for normal development, it has become clear that coordination of the molecular signals responsible for specification of these domains is essential for normal development. In fact, if the signals regulating laterality are disrupted, then midline and other defects can occur as has been observed in cases of heterotaxy, presumably because of a disruption in this coordinated signaling effort. Thus, the origins of the defects commonly observed in the VACTERL association may be due to altered signaling responsible for establishing the left-right axis. © 2015 Wiley Periodicals, Inc.

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