American Journal of Medical Genetics Part A 

About: American Journal of Medical Genetics Part A is an academic journal. The journal publishes majorly in the area(s): Population & Exome sequencing. It has an ISSN identifier of 1552-4825. Over the lifetime, 9508 publications have been published receiving 198463 citations.

Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service.

Abstract: Autosomal dominantly inherited tumor-prone syndromes are a substantial health problem and are amenable to epidemiologic studies by combining cancer surveillance registries with a genetic register (GR)-based approach. Knowledge of the frequency of the conditions provides a basis for appropriate health-resources allocations. GRs for five tumor-prone syndromes were established in the Manchester region of North West England in 1989 and 1990. Mapping birth dates of affected individuals from families onto regional birth rates has allowed an estimate of birth incidence, disease prevalence, and de novo mutation rates. Disease prevalence in order of frequency were for neurofibromatosis type 1 (NF1): 1 in 4,560; familial adenomatous polyposis (FAP): 1 in 18,976; nevoid basal cell carcinoma [Gorlin syndrome (GS)]: 1 in 30,827; neurofibromatosis type 2 (NF2) 1 in 56,161; and von Hippel Lindau (VHL) 1 in 91,111. Best estimates for birth incidence were: 1 in 2,699; 1 in 8,619; 1 in 14,963, 1 in 33,000; and 1 in 42,987, respectively. The proportions due to de novo mutation were: 42% (NF1); 16% (FAP); 26% (GS); 56% (NF2); and 21% (VHL). Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and we provide the first estimates of birth incidence and de novo mutation rate for GS.

Nosology and classification of genetic skeletal disorders : 2010 revision

Abstract: Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

Endogenous hydrogen sulfide overproduction in Down syndrome.

Abstract: The cystathionine beta synthase (CBS) gene is localized on chromosome 21 (21q22.3). This enzyme is one of three enzymes able to produce hydrogen sulfide. CBS is overexpressed in Down syndrome with levels 166% of normal values in fibroblasts [Chadefaux et al., 1985] and 1,200% in myeloblasts [Taub et al., 1999]. The CBS overexpression could induceanoverproduction ofhydrogen sulfide in Down syndrome patients, and this overproduction is potentially able to induce some of the clinical signs of Down syndrome such as hypotonia and mental retardation. As thiosulfate is the main catabolite of hydrogen sulfide [Kangas and Savolainen, 1987], we compared the levels of this molecule in the urine of Down syndrome patients and control subjects. Human erythrocytes containvarious formsofhemoglobin.These include sulfhemoglobin, which is formed by transformation of the ferric derivative of hemoglobin, methemoglobin. Sulfhemoglobin production requires hydrogen sulfide (or another sulfide) andmethemoglobin [Nichols et al., 1968]. The determination of sulfhemoglobin in erythrocytes was therefore also used to assess hydrogen sulfide production in Down syndrome. Informed consent was obtained from Down syndrome patients and their parents and from controls. The subjects were assigned to three groups. Group 1 (diet-matched pairs) consisted of 21 pairs of subjects (17 of them were included in a previously published study [Belardinelli et al., 2001]. In each volunteer family, one Down syndrome subject and one relative (mother or father in most families, brother or sister in rare cases) were given identical diets. This group consisted of 13 male and 8 female Down syndrome subjects and matched controls (10 male and 11 female). Sulfur compounds were excluded from the daily treatments of Downsyndromepatientsandcontrols.Group2consisted of 30 patients with Down syndrome (19 male and 11 female) and 20 controls (volunteers from the laboratory; 10 male and 10 female). In this group, age distribution was similar for Down syndrome patients and controls (Table I). The first urine produced in the morning was collected from the subjects of groups 1 and 2 in vials containing boric acid used as a preservative. Thiosulfate was determined in urine by colorimetry after chromatographic separation [Voroteliak et al., 1993]. Creatinine was determined by the manual Jaffe method. Group 3 consisted of 60 Down syndrome patients (33 male and 27 female) and 60 age-matched controls (35 male and 25 female). Venous blood was withdrawn in fasting subjects of group 3; erythrocytes were separated by centrifugation and hemolysates were frozen until use. Sulfhemoglobin was determined by spectrophotometry and the results are expressed as ratio of absorbance (A) at various wawelengths: (A622 nm A636 nm)/(A535 nmþA560 nm) 0.5 10. This ratio was used because it is not affected by differences between the respective concentrations of oxygenated and unoxygenated hemoglobin. A significant difference was observed in the urinary excretion of thiosulfate between Down syndrome patients and relatives of group 1 (diet-matched pairs) (Table I). In group 2, statistical analysis indicates that the differences in thiosulfate excretion persisted. To confirm that hydrogen sulfide was overproduced in Down syndrome patients, we studied erythrocyte sulfhemoglobin content in subjects of group 3. The wawelength ratios were 2.51 0.04 and 2.00 0.08 (SEM) for patientswithDownsyndrome and controls, respectively (P<0.001). We obtained two different types of evidence for the overproduction of hydrogen sulfide in Down syndrome patients. The main function of CBS is to catalyze the first step of transsulphuration pathway, producing cysteine from homocysteine. In vivo, the high level of CBS activity in Down syndrome results in low concentrations of the substrate of CBS (homocysteine) in plasma [Chadefaux et al., 1988]. CBS also has another enzymatic activity: the production of hydrogen sulfide from cysteine [Stipanuck and Beck, 1982]. The endogenous productionofhydrogensulfidecanbeestimatedbymonitoring thiosulfate excretion in urine (31 mmoles/day in control adults) [Sorbo and Ohman, 1978]. After hydrogen sulfide poisoning, the excretion of thiosulfate in urine increased significantly [Kangas and Savolainen, *Correspondence to: Pierre Kamoun, Biochimie B–Tour Lavoisier, Hôpital Necker Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: pierre.kamoun@nck.ap-hop-paris.fr

Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment

Abstract: Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Angelman syndrome 2005: updated consensus for diagnostic criteria.

Abstract: In 1995, a consensus statement was published for the purpose of summarizing the salient clinical features of Angelman syndrome (AS) to assist the clinician in making a timely and accurate diagnosis. Considering the scientific advances made in the last 10 years, it is necessary now to review the validity of the original consensus criteria. As in the original consensus project, the methodology used for this review was to convene a group of scientists and clinicians, with experience in AS, to develop a concise consensus statement, supported by scientific publications where appropriate. It is hoped that this revised consensus document will facilitate further clinical study of individuals with proven AS, and assist in the evaluation of those who appear to have clinical features of AS but have normal laboratory diagnostic testing.