Dorothy K Grange

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (57)265.08 Total impact

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    ABSTRACT: ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome, a distinct multi-organ disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of Cantú syndrome (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether co-expressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in Cantú syndrome, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from Kir6-independent SUR2 function. This article is protected by copyright. All rights reserved.
    Human Mutation 04/2014; · 5.21 Impact Factor
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    ABSTRACT: New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
    Molecular Genetics and Metabolism 03/2014; · 2.83 Impact Factor
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.
    Molecular genetics & genomic medicine. 03/2014; 2(2):115-23.
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    ABSTRACT: A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine the relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (<5, 5.0-9.9, and ≥10years of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes and that Phe control should not be liberalized as children with PKU age.
    Molecular Genetics and Metabolism 01/2014; · 2.83 Impact Factor
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    ABSTRACT: The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6% of all samples tested clinically and have been identified as a major cause of autism spectrum disorders, developmental delay, behavioral abnormalities, and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size, obesity, dysmorphism, and congenital abnormalities. In this report, we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients, nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29,366,195 and 30,306,956 (hg19) with a minimal size of 555 kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However, additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis, surveillance and genetic counseling of patients with 16p11.2 rearrangement. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; · 2.30 Impact Factor
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    ABSTRACT: Background Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria. Methods In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054. Findings 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89–106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection. Interpretation Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing. Funding BioMarin Pharmaceutical.
    01/2014;
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    ABSTRACT: For pregnant women with phenylketonuria (PKU), maintaining blood phenylalanine (Phe) < 360 μmol/L is critical due to the toxicity of elevated Phe to the fetus. Sapropterin dihydrochloride (sapropterin) lowers blood Phe in tetrahydrobiopterin (BH4) responsive patients with PKU, in conjunction with a Phe-restricted diet, but clinical evidence supporting its use during pregnancy is limited. As of June 3, 2013, the Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry contained data from 21 pregnancies – in women with PKU who were either treated with sapropterin before (N = 5) or during (N = 16) pregnancy. Excluding data for spontaneous abortions (N = 4), the data show that the mean of median blood Phe [204.7 ± 126.6 μmol/L (n = 14)] for women exposed to sapropterin during pregnancy was 23% lower, and had a 58% smaller standard deviation, compared to blood Phe [267.4 ± 300.7 μmol/L (n = 3)] for women exposed to sapropterin prior to pregnancy. Women on sapropterin during pregnancy experienced fewer blood Phe values above the recommended 360 μmol/L threshold. When median blood Phe concentration was < 360 μmol/L throughout pregnancy, 75% (12/16) of pregnancy outcomes were normal compared to 40% (2/5) when median blood Phe was > 360 μmol/L. Severe Adverse Events identified by the investigators as possibly related to sapropterin use were premature labor (N = 1) and spontaneous abortion (N = 1) for the women and hypophagia for the offspring [premature birth (35w4d), N = 1]. One congenital malformation (cleft palate) of unknown etiology was reported as unrelated to sapropterin. Although there is limited information regarding the use of sapropterin during pregnancy, these sub-registry data show that sapropterin was generally well-tolerated and its use during pregnancy was associated with lower mean blood Phe. Because the teratogenicity of elevated maternal blood Phe is without question, sapropterin should be considered as a treatment option in pregnant women with PKU who cannot achieve recommended ranges of blood Phe with dietary therapy alone.
    Molecular Genetics and Metabolism 01/2014; · 2.83 Impact Factor
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    ABSTRACT: Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2013; · 2.30 Impact Factor
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    ABSTRACT: Tetrahydrobiopterin (BH4) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH4 responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH4. Compared with baseline, Phe in these responders decreased by 51% during a 4week screening period after initiation of treatment and remained lowered by 37% over the 6month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH4 treatment within a single study.
    Molecular Genetics and Metabolism 07/2013; · 2.83 Impact Factor
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    ABSTRACT: Previous studies have revealed white matter abnormalities in the brains of individuals with phenylketonuria (PKU), but the microstructural nature of these abnormalities and their relationship to phenylalanine (Phe) levels and cognitive outcomes are poorly understood. In the current study, the microstructural integrity of white matter in 29 individuals with early-treated PKU and 12 healthy controls was examined using two complementary diffusion tensor imaging (DTI) approaches: region-of-interest (ROI) based analysis and voxel-wise tract based spatial statistics (TBSS) analysis. Relationships among DTI, executive abilities, and Phe level findings were explored. DTI revealed widespread lowering of mean diffusivity (MD) in the white matter of the PKU group in comparison with the control group. Executive abilities were also poorer for individuals with PKU than controls. Within the PKU group, lower MD was associated with higher Phe level and poorer executive abilities. These findings are the first to demonstrate the interplay among microstructural white matter integrity, executive abilities, and Phe control in individuals with PKU.
    Molecular Genetics and Metabolism 04/2013; · 2.83 Impact Factor
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    ABSTRACT: Response monitoring (post-error slowing) and inhibitory control (commission errors) were examined in children with phenylketonuria (PKU) and controls (6-18 years) using Go/No-Go tasks with higher (PKU n = 37; control n = 55) versus lower (PKU n = 24; control n = 25) non-target expectancy. On both tasks children with PKU exhibited impaired monitoring and inhibitory control, but the post-error slowing pattern was different. With higher expectancy children with PKU slowed more (less efficient monitoring) and with lower expectancy slowed less (less monitoring) than controls. No effects of age or phenylalanine level were noted. These results indicate that expectancy differentially effects monitoring and inhibitory control in PKU.
    Developmental Neuropsychology 04/2013; 38(3):139-52. · 2.90 Impact Factor
  • Colin G Nichols, Gautam K Singh, Dorothy K Grange
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    ABSTRACT: ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP(2) and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities.
    Circulation Research 03/2013; 112(7):1059-72. · 11.86 Impact Factor
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    ABSTRACT: Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ∼50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ∼70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.
    The American Journal of Human Genetics 12/2012; · 11.20 Impact Factor
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    ABSTRACT: Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder that often results in neuropsychological impairment, even in individuals treated early and continuously. This study was conducted to examine processing speed, variability in processing speed, and the relationship between processing speed variables and executive abilities in children with early and continuously treated PKU. Method: Participants were 42 children with PKU and 81 typically developing children from 7 to 18 years of age. Children completed 3 computerized reaction time (RT) tasks (simple RT, go/no-go, stimulus-response compatibility) and 7 tasks assessing executive abilities (working memory, inhibitory control, strategic processing). Results: Performance of children with PKU was significantly slower and more variable than that of controls across the 3 tasks administered. When age was considered, it was shown that processing speed improved with age to a comparable degree for both groups. Variability in processing speed, however, decreased more with age for the PKU than control group, reflecting the fact that variability in younger, but not older, children with PKU was greater than that of controls. With regard to executive abilities, processing speed and variability contributed to performance on most, but not all, executive tasks; and after controlling for processing speed and variability, executive impairments were still identified in working memory and inhibitory control (not strategic processing). Conclusions: These findings indicate that information processing is slower and less efficient in children with PKU. In addition, processing speed and variability contribute to some, but not all, of the impairments in executive abilities observed in children with PKU. (PsycINFO Database Record (c) 2012 APA, all rights reserved).
    Neuropsychology 08/2012; · 3.58 Impact Factor
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    ABSTRACT: Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.
    The American Journal of Human Genetics 05/2012; 90(6):1094-101. · 11.20 Impact Factor
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    ABSTRACT: Chromosome 2p15p16.1 microdeletion is an emerging syndrome recently described in patients with dysmorphic facial features, congenital microcephaly, mild to moderate developmental delay and neurodevelopmental abnormalities. Using clinical ultra-high resolution Affymetrix SNP 6.0 array we identified a de novo interstitial deletion on the short arm of chromosome 2, spanning approximately 2.5 Mb in the cytogenetic band position 2p15p16.1, in a female infant with characteristic features of 2p15p16.1 deletion syndrome including severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect. We further redefined the previously reported critical region, supporting the presence of a newly recognized microdeletion syndrome involving haploinsufficiency of one or more genes deleted within at least a 1.1 Mb segment of the 2p15p16.1 region.
    European journal of medical genetics 04/2012; 55(8-9):485-9. · 1.57 Impact Factor
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    ABSTRACT: X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. Array CGH analysis was performed using chromosomal microarray with ∼105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. A novel ∼0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.
    Journal of Medical Genetics 12/2011; 48(12):840-50. · 5.70 Impact Factor
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    ABSTRACT: To determine how US newborn dried bloodspot screening (NDBS) programs obtain patient-level data on clinical genetic counseling services offered to families of newborns identified through newborn NDBS and the extent to which newborns and their families receive these services. These data should serve to inform programs and lead to improved NDBS follow-up services. Collaborations were established with three state NDBS programs that reported systematically tracking genetic counseling services to newborns and their families identified through NDBS. A study protocol and data abstraction form were developed and IRB approvals obtained. Data from three state NDBS programs on a total of 151 patients indicated that genetic services are documented systematically only by metabolic clinics, most often by genetic counselors. Data from 69 endocrinology patients indicated infrequent referrals for genetic services; as expected higher for congenital adrenal hyperplasia than congenital hypothyroidism. Endocrinology patients were often counseled by physicians. While systematic tracking of genetic counseling services may be desirable for quality assurance of NDBS follow-up services, current systems do not appear conducive to this practice. Clinical records are not typically shared with NDBS programs and tracking of follow-up clinical genetic services has not been generally defined as a NDBS program responsibility. Rather, tracking of clinical services, while recognized as useful data, has been viewed by NDBS programs as a research project. The associated IRB requirements for patient-related research may pose an additional challenge. National guidance for NDBS programs that define quality genetic service indicators and monitoring responsibilities are needed. US experiences in this regard may provide information that can assist developing programs in avoiding tracking issues.
    Journal of community genetics 12/2011; 2(4):191-200.
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    ABSTRACT: We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers. Hum Mutat 33:165–179, 2012. © 2011 Wiley Periodicals, Inc.
    Human Mutation 11/2011; 33(1):165 - 179. · 5.21 Impact Factor
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    American Journal of Medical Genetics Part A 09/2011; 155A(10):2589-92. · 2.30 Impact Factor

Publication Stats

766 Citations
230 Downloads
4k Views
265.08 Total Impact Points

Institutions

  • 2003–2014
    • Washington University in St. Louis
      • • Department of Pediatrics
      • • Department of Psychology
      San Luis, Missouri, United States
  • 2005–2011
    • University of Washington Seattle
      • • Department of Pediatrics
      • • Department of Psychology
      • • Division of Medical Genetics
      Seattle, WA, United States