bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and clinical features associated with CFTR gene rearrangements in Italian population: identification of a new duplication and recurrent deletions
Authors: Paracchini V , Seia M , Coviello D , Porcaro L , Costantino L , Capasso P , Degiorgio D , Padoan R , Corbetta C , Claut L , Costantini D , Colombo C
Published: January 2009

Cystic fibrosis (CF) is mainly caused by small deletions or missense mutations in the CFTR gene. The CF mutation database lists more than 35 large rearrangements that may escape detection using polymerase chain reaction‐base techniques. The Innogenetics assay, the denaturing high‐performance liquid chromatography and sequencing screening showed a mutation detection rate of 92.6% in our population. We report here the results of multiplex ligation‐dependent probe amplification (MLPA) screening for CFTR gene rearrangements, performed on the unidentified alleles of our CF patients. Our sample population consists of 692 non‐related Italian CF patients (for a total of 1384 alleles), followed at CF Centres in the Lombardia Region. MLPA analysis was performed in 49 patients who still had one or two unidentified alleles (for a total of 52 unidentified alleles) after extensive analysis of CFTR gene. All patients who were studied had the classical form of CF. We characterized nine different deletions and a new duplication. The deletion of exons 22–23 (7/82) was the most frequent in our cohort. The search for deletion/duplications of the CFTR gene has made it possible to reach a 94.1% detection rate, with an improvement (1.6%) of the carrier detection rate in the Italian population.
Prader–Willi syndrome phenocopy due to duplication of Xq21.1–q21.31, with array CGH of the critical region
Authors: Gabbett MT , Peters GB , Carmichael JM , Darmanian AP , Collins FA
Published: January 2009

We report on a 4‐year‐old male with an interstitial tandem duplication of Xq21.1–q21.31 who presented with clinical features of Prader–Willi syndrome (PWS). The duplication was maternally inherited. Abnormalities of the X chromosome have previously been reported in association with a PWS phenotype, but to date, specific duplications of Xq21.1–q21.31 have not. We refined the chromosomal breakpoints seen on initial G‐banded karyotyping in our case with comparative genomic hybridization by microarray (array CGH). The duplication was between 11.1 and 14.4 Mb in length and overlaps with three loci to which mental retardation with PWS‐like features have been previously mapped, showing the utility of array CGH in helping to identify candidate genes. We conclude that duplication of chromosomal region Xq21.1–q21.31 potentially results in a PWS‐like phenotype. Reviewing the literature on similar duplications, we further conclude that distal Xq duplications can result in features typically seen in infants with PWS, while proximal duplications can result in features typically seen in older children and adults with PWS. Duplications of chromosome Xq should be considered in the differential diagnosis of PWS, especially in males.
CMT4J: Charcot–Marie–Tooth disorder caused by mutations in FIG4
Authors: De Leeuw CN
Published: January 2009

Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J Chow et al. (2007) Nature 448: 68–72. Epub 17 June 2007
The impact of genetic testing for Crohn’s disease, risk magnitude and graphical format on motivation to stop smoking: an experimental analogue study
Authors: Wright AJ , Takeichi C , Whitwell SCL , Hankins M , Marteau TM
Published: January 2009

Genetic tests may motivate risk‐reducing behaviour more than other types of tests because they generate higher risk magnitudes and because their results have high personal relevance. To date, trial designs have not allowed the disentangling of the effects of these two factors. This analogue study examines the independent impacts of risk magnitude and provenance, and of risk display type, on motivation to quit smoking. A total of 180 smokers were randomly allocated to one of the 18 Crohn’s disease risk vignettes in a 3 (risk provenance: family history. genetic test mutation positive. genetic test mutation negative) × 3 (risk magnitude: 3%, 6%, 50%) × 2 (display: grouped or dispersed icons) design. The 50% group had significantly higher intentions to quit than the 3% group. A significant risk provenance × magnitude interaction showed that participants in 50% or 6% groups were equally motivated, regardless of risk provenance, while participants in the 3% group had higher intentions associated with a mutation negative result than with a result based on family history alone. Grouped icon displays were more motivating than the dispersed icons. Using genetic tests to estimate risks of common complex conditions may not motivate behaviour change beyond the impact of the numerical risk estimates derived from such tests.
Homeobox genes in vertebrate forebrain development and disease
Authors: Wigle JT , Eisenstat DD
Published: January 2009

Homeobox genes are an evolutionarily conserved class of transcription factors that are key regulators of developmental processes such as regional specification, patterning, migration and differentiation. In both mouse and humans, the developing forebrain is marked by distinct boundaries of homeobox gene expression at different developmental time points. These genes regulate the patterning of the forebrain along the dorsal/ventral and rostral/caudal axes and are also essential for the differentiation of specific neuronal subtypes. Inhibitory interneurons that arise from the ganglionic eminences and migrate tangentially to the neocortex and hippocampus are dramatically affected by mutations in several homeobox genes. In this review, we discuss the identification, expression patterns, loss‐ and/or gain‐of‐function models, and confirmed transcriptional targets for a set of homeobox genes required for the correct development of the forebrain in the mouse. In humans, mutations of homeobox genes expressed in the forebrain have been shown to result in mental retardation, epilepsy or movement disorders. The number of homeobox genes currently linked to human nervous system disease is surprisingly low, perhaps reflecting the essential functions of these genes throughout embryogenesis or the degree of functional redundancy during central nervous system development.
Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families
Authors: Evans DGR , Young K , Bulman M , Shenton A , Wallace A , Lalloo F
Published: January 2009

While there are many reports in the literature of mutation testing of BRCA1 and BRCA2 in breast/ovarian cancer families, the question of which type of ovarian cancers are relevant still pertains. We have undertaken whole gene screening including multiple ligation‐dependent probe amplification in an affected individual within 442 unrelated non‐Jewish families containing at least one reported ovarian cancer diagnosed less than 50 years or at any age with family history of breast or ovarian cancer for mutations in BRCA1 and BRCA2. A total of 166 mutations were identified 110 (25%) in BRCA1 and 56 (13%) in BRCA2. In families without confirmation of ovarian diagnosis, the detection rate drops significantly. In families fulfilling Breast Cancer Linkage Consortium (BCLC) criteria with confirmed ovarian cancer cases, the mutation detection frequency was 80%. If only BCLC families with unconfirmed ovarian cancers were included, the detection rate dropped to 36% when a relevant ovarian cancer diagnosis was not confirmed. In BCLC families containing only one ovarian cancer, BRCA2 accounted for 45% of identified mutations. No mutations were identified in affected individuals with borderline or mucinous tumours. Detection rates dropped below the 10/20% international thresholds in a number of families with unconfirmed ovarian cancers. Borderline/mucinous pathology substantially reduces the likelihood of identifying a BRCA1/2 mutation. Strenuous efforts should be made to confirm ovarian pathology if the lack of confirmation or refuting the diagnosis would decrease a family’s likelihood of mutation detection below screening thresholds. In the UK, a higher proportion of families harbour BRCA2 pathogenic mutations than predicted from previous studies.
Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48‐month longitudinal cohort study
Authors: Sims KB , Pastores GM , Weinreb NJ , Barranger J , Rosenbloom BE , Packman S , Kaplan P , Mankin H , Xavier R , Angell J , Fitzpatrick MA , Rosenthal D
Published: January 2009

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48‐month, prospective, non‐randomized, open‐label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase‐naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre‐treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual‐energy X‐ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near‐normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.
Mental retardation in a girl with a subtelomeric deletion on chromosome 20q and complete deletion of the myelin transcription factor 1 gene (MYT1)
Authors: Kroepfl T , Petek E , Schwarzbraun T , Kroisel PM , Plecko B
Published: January 2009

A great number of syndromes and inborn errors of metabolism associated with impaired development have been observed, but the aetiology of mental retardation remains unclear in a considerable proportion of cases. Here, we present the clinical and molecular data from a patient with a new de novo subtelomeric deletion on chromosome 20 [46,XX.ish del(20)(qter‐)]. For further refinement, bacterial artificial chromosome clones are used. The deletion spans exactly two genes called MYT1 and PCMTD2. Both genes play an important role in myelination and regulating neural differentiation. Loss of these two genes seems to be responsible for the severe mental retardation and mild facial dysmorphic features in our young patient. It might show the phenotypic picture of this specified deletion.
Mutations in sarcomeric protein genes not only lead to cardiomyopathy but also to congenital cardiovascular malformations
Authors: Wessels Marja W. , Willems Patrick J.
Published: January 2009

Noncompaction of the ventricular myocardium is associated with de novo mutation in the beta‐myosin heavy chain gene Budde et al. (2007) PLoS ONE 2: e1362

Homozygosity for a novel splice site mutation in the cardiac myosin‐binding protein C gene causes severe neonatal hypertrophic cardiomyopathy Xin et al. (2007) Am J Med Genet 143: 2662–2667

Alpha‐cardiac actin mutations produce atrial septal defects Matsson et al. (2008) Hum Mol Genet 17: 256–265
ATM germline mutations in Spanish early‐onset breast cancer patients negative for BRCA1/BRCA2 mutations
Authors: Brunet J , Gutiérrez‐Enríquez S , Torres A , Bérez V , Sanjosé S , Galceran J , Izquierdo À , Menéndez JA , Gumà J , Borràs J
Published: January 2009

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early‐onset BC. Forty‐three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early‐onset BC.
Little people, big discovery
Authors: Kobelka CE
Published: January 2009

Mutations in the pericentrin (PCNT) gene cause primordial dwarfism Anita Rauch et al. (2008) Science 319: 816–819
The ups and downs of holoprosencephaly: dorsal versus ventral patterning forces
Authors: Fernandes M , Hébert JM
Published: January 2009

Holoprosencephaly (HPE), characterized by incomplete separation of forebrain and facial components into left and right sides, is a common developmental defect in humans. It is caused by both genetic and environmental factors and its severity covers a wide spectrum of phenotypes. The genetic interactions underlying inherited forms of HPE are complex and poorly understood. Animal models, in particular mouse mutants, are providing a growing understanding of how the forebrain develops and how the cerebral hemispheres become split into left and right sides. These insights, along with the characterization to date of some of the genes involved in human HPE, suggest that two distinct mechanisms underlie the major classes of HPE, ‘classic’ and midline interhemispheric (MIH). Disruption either directly or indirectly of the ventralizing effect of sonic hedgehog signaling appears central to all or most forms of classic HPE, while disruption of the dorsalizing effect of bone morphogenetic protein signaling may be key to cases of MIH HPE.
CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine
Authors: Stam AH , Vanmolkot KRJ , Kremer HPH , Gärtner J , Brown J , Leshinsky‐Silver E , Gilad R , Kors EE , Frankhuizen WS , Ginjaar HB , Haan J , Frants RR , Ferrari MD , Van Den Maagdenberg AMJM , Terwindt GM
Published: January 2009

Of the 18 missense mutations in the CACNA1A gene, which are associated with familial hemiplegic migraine type 1 (FHM1), only mutations S218L, R583Q and T666M were identified in more than two independent families. Including the four novel families presented here, of which two represent de novo cases, the R1347Q mutation has now been identified in six families. A genotype–phenotype comparison of R1347Q mutation carriers revealed a wide clinical spectrum ranging from (trauma triggered) hemiplegic migraine with and without ataxia, loss of consciousness and epilepsy. R1347Q is the third most frequent mutation in hemiplegic migraine patients and should therefore be screened with priority for confirmation of clinical diagnosis. This study clearly demonstrates that the availability of multiple families better reflects the full clinical spectrum associated with FHM1 mutations.
Mowat–Wilson syndrome: an underdiagnosed syndrome?
Authors: Engenheiro E , Møller RS , Pinto M , Soares G , Nikanorova M , Carreira IM , Ullmann R , Tommerup N , Tümer Z
Published: January 2009

Mowat–Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) gene at 2q22. MWS was first described in 1998 and the causative gene was delineated in 2001. Since then, 115 different mutations of ZEB2 have been published in association with this syndrome in 161 individuals. However, recent reports suggest that due to the variability of the congenital abnormalities, this syndrome may still be underdiagnosed. We report two unrelated patients with MWS where the clinical diagnosis was established only after finding of disruption of the ZEB2 gene by a balanced translocation breakpoint and an interstitial microdeletion, respectively.
Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure
Authors: Schüle B , Armstrong DD , Vogel H , Oviedo A , Francke U
Published: January 2009

Non‐mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal‐onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi‐stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post‐mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9‐nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2‐/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.
FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations
Authors: Attanasio M , Lapini I , Evangelisti L , Lucarini L , Giusti B , Porciani MC , Fattori R , Anichini C , Abbate R , Gensini GF , Pepe G
Published: January 2009

Fibrillin‐1 gene (FBN1) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium‐binding epidermal growth factor‐like domains. We found preferential associations between The Cys‐missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1–10 and 59–65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.
Knowledge and impressions regarding the concept of mutation among Japanese university students
Authors: Ando N , Saito Y , Takemura K , Takada F , Iwamitsu Y
Published: January 2009

Although the term mutation is frequently used in genetic counseling, it may carry negative connotations and create misunderstanding. Our objective was to investigate the relationship between the impressions regarding three Japanese terms mutation of gene, change of gene, and lesion of gene as well as to investigate the depth of understanding regarding mutation. A total of 175 university students and auditing students were included and responded to two questionnaires that were Impressions regarding the term in the semantic differential method and Knowledge about the concept of mutation. In factor analysis, three factors (Value, Change Rate, and Intention) were extracted. Participants were divided into three groups depending on their knowledge, and a two‐way analysis of variance (Term × Knowledge Group) was conducted on the factor score for each. Results showed that the main effect of the ‘Term’ was significant for the Value Factor and that interaction was significant for the Change Rate Factor, and that the main effect of Knowledge Group was significant for the Intention Factor. The findings suggest that healthcare professionals should demonstrate an awareness of varying impressions of the different terms used to refer to the identical concepts of mutation. This is of particular importance when communicating with patients and their families.
The skeletal manifestations of the congenital disorders of glycosylation
Authors: Coman D , Irving M , Kannu P , Jaeken J , Savarirayan R
Published: January 2009

The congenital disorders of glycosylation (CDG) are a rapidly expanding disease group with protean presentations. Specific end‐organ involvement leads to significant morbidity and mortality, and the skeletal manifestations are often not appreciated, apart from the common association of osteopaenia with CDG‐Ia. We performed a literature review of all documented skeletal manifestations in reported CDG patients, revealing a diverse range of skeletal phenotypes. We discuss the possible underlying mechanisms of these skeletal manifestations observed in CDG that are important and frequently under‐recognized.
Investigating genetic discrimination in Australia: a large‐scale survey of clinical genetics clients
Authors: Taylor S , Treloar S , Barlow‐Stewart K , Stranger M , Otlowski M
Published: January 2009

We report first results from the Australian Genetic Discrimination Project of clinical genetics services clients’ perceptions and experiences regarding alleged differential treatment associated with having genetic information. Adults (n = 2667) who had presented from 1998 to 2003 regarding predictive or presymptomatic testing for designated mature‐onset conditions were surveyed; 951/1185 respondents met inclusion criteria for current asymptomatic status. Neurological conditions and familial cancers were primary relevant conditions for 87% of asymptomatic respondents. Specific incidents of alleged negative treatment, reported by 10% (n = 93) of respondents, occurred in life insurance (42%), employment (5%), family (22%), social (11%) and health (20%) domains. Respondents where neuro‐degenerative conditions were relevant were more likely overall to report incidents and significantly more likely to report incidents in the social domain. Most incidents in the post‐test period occurred in the first year after testing. Only 15% of respondents knew where to complain officially if treated negatively because of genetics issues. Recommendations include the need for increased community and clinical education regarding genetic discrimination, for extended clinical genetics sector engagement and for co‐ordinated monitoring, research and policy development at national levels in order for the full benefits of genetic testing technology to be realised.
A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot–Marie–Tooth disease in an Amish family
Authors: Xin B , Puffenberger E , Nye L , Wiznitzer M , Wang H
Published: January 2009

Charcot–Marie–Tooth disease (CMT) constitutes a large group of genetically heterogeneous disorders of the peripheral nervous system. Autosomal recessive forms of CMT are less common in the general population but account for the vast majority of CMT phenotypes in communities with a high prevalence of consanguinity. At least 10 genetic loci cause autosomal recessive forms of CMT. Mutations in the ganglioside‐induced differentiation‐associated protein 1 (GDAP1) gene are among the most frequent genetic causes of autosomal recessive forms of CMT. To date, 28 mutations in GDAP1 gene have been linked with the disease. Here, we report a novel GDAP1 mutation in an Old Order Amish family with CMT. To ascertain the Amish CMT locus, we performed a genome‐wide single nucleotide polymorphism (SNP) analysis on one of three patients from a consanguineous pedigree. Assuming mutation homogeneity, the analysis sought large homozygous SNP blocks that also contained known CMT loci. The largest homozygous SNP block in the patient was localized to chromosome 8q13.1‐21.3 and contained the GDAP1 gene. Sequence analysis revealed a novel homozygous mutation, c.692C>T, at codon 231 (p.P231L) in exon 5 of GDAP1 in all patients. Neither the unaffected individuals in the family nor the healthy control samples were homozygous for this mutation. Our findings suggested that this novel mutation in GDAP1 gene is associated with an autosomal recessive form of CMT in Ohio Old Order Amish community.
Multiple independent second‐site mutations in two siblings with somatic mosaicism for Wiskott–Aldrich syndrome
Authors: Boztug K , Germeshausen M , Avedillo Díez I , Gulacsy V , Diestelhorst J , Ballmaier M , Welte K , Maródi L , Chernyshova LI , Klein C
Published: January 2009

Wiskott–Aldrich syndrome (WAS) is an X‐linked primary immunodeficiency disorder associated with microthrombocytopenia, eczema, autoimmunity and predisposition to malignant lymphoma. Although rare, few cases of somatic mosaicism have been published in WAS patients to date. We here report on two Ukrainian siblings who were referred to us at the age of 3 and 4 years, respectively. Both patients suffered from severe WAS caused by a nonsense mutation in exon 1 of the WAS gene. In both siblings, flow cytometric analysis revealed the presence of Wiskott–Aldrich syndrome protein (WASp)‐positive and WASp‐negative cell populations among T and B lymphocytes as well as natural killer (NK) cells. In contrast to previously described cases of revertant mosaicism in WAS, molecular analyses in both children showed that the WASp‐positive T cells, B cells, and NK cells carried multiple different second‐site mutations, resulting in different missense mutations. To our knowledge, this is the first report describing somatic mosaicism in WAS patients caused by several independent second‐site mutations in the WAS gene.
Birth defects before epigenesis
Authors: Tucker HA
Published: January 2009

Physicians have tried to explain the origins of birth defects since antiquity. In early humoralist models, fetal anomalies were most often understood in terms of quantity and quality of male and female seed. Maternal imagination was also considered a key environmental influence on fetal development from Hippocrates, Galen, and into late 17th century preformation.
Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes
Authors: Menko FH , Kneepkens CMF , De Leeuw N , Peeters EAJ , Van Maldergem L , Kamsteeg EJ , Davidson R , Rozendaal L , Lasham CA , Peeters‐Scholte CMP , Jansweijer MC , Hilhorst‐Hofstee Y , Gille JJP , Heins YM , Nieuwint AWM , Sistermans EA
Published: January 2009

Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effect of the deletion of both genes would explain the condition. Subsequently, however, a patient with a larger 10q23 deletion including the same genes but with a mild clinical phenotype was identified. Here, we present four additional patients with 10q23 microdeletions involving the PTEN and BMPR1A genes. The sizes of the deletions were analyzed using single nucleotide polymorphism array analysis. All patients had macrocephaly, dysmorphic features, retardation and congenital abnormalities. One patient developed colorectal cancer. However, only one case had disease onset before 2 years of age and severe symptoms requiring colectomy. No clear correlation was found between ages at onset or severity of gastrointestinal symptoms and the sizes of the deletions. We conclude that patients with 10q23 microdeletions involving the PTEN and BMPR1A genes have variable clinical phenotypes, which cannot be explained merely by the deletion sizes. The phenotypes are not restricted to severe infantile juvenile polyposis but include childhood‐onset cases with macrocephaly, retardation, mild gastrointestinal symptoms and possibly early‐onset colorectal cancer.
Genetic aspects of human congenital diaphragmatic hernia
Authors: Pober BR
Published: January 2009

Congenital diaphragmatic hernia (CDH) is a common major malformation affecting 1/3000–1/4000 births, which continues to be associated with significant perinatal mortality. Much current research is focused on elucidating the genetics and pathophysiology contributing to CDH to develop more effective therapies. The latest data suggest that many cases of CDH are genetically determined and also indicate that CDH is etiologically heterogeneous. The present review will provide a brief summary of diaphragm development and model organism work most relevant to human CDH and will primarily describe important human phenotypes associated with CDH and also provide recommendations for diagnostic evaluation of a fetus or infant with CDH.
Alu‐related 5q35 microdeletions in Sotos syndrome
Authors: Mochizuki J , Saitsu H , Mizuguchi T , Nishimura A , Visser R , Kurotaki N , Miyake N , Unno N , Matsumoto N
Published: January 2009

Haploinsufficiency of the NSD1 gene due to 5q35 microdeletions or intragenic mutations causes Sotos syndrome (SoS). In 46 of the 49 Japanese deletion cases, common deletion breakpoints were located at two flanking low copy repeats (LCRs), implying that non‐allelic homologous recombination (NAHR) between LCRs is the major mechanism for the common deletion. In the other three cases of atypical deletions, the mechanism(s) of deletions remains unanswered. We characterized the atypical microdeletions using fluorescence in situ hybridization (FISH), quantitative real‐time polymerase chain reaction (qPCR), and Southern blot hybridization. All the deletion breakpoints in the three cases were successfully determined at the nucleotide level. Two deletions are 1.07 Mb (SoS19) and 1.23 Mb (SoS109) in size, and another consisted of two deletions with sizes of 28 kb and 0.72 Mb, intervened by an intact 29‐kb segment (SoS44). All deletions were smaller than a typical 1.9‐Mb common deletion. Alu elements were identified in both deletion breakpoints in SoS19, one of deletion breakpoints in SoS109, and both deletion breakpoints of the proximal 28‐kb deletion in SoS44. Alu‐mediated NAHR is strongly suggested at least in two of atypical deletions. Finally, qPCR is a very useful method to determine deletion breakpoints even in repeat‐related regions.
Genetic variations in the leptin and leptin receptor genes are associated with type 2 diabetes mellitus and metabolic traits in the Korean female population
Authors: Han HR , Ryu H‐J , Cha HS , Go MJ , Ahn Y , Koo BK , Cho YM , Lee HK , Cho NH , Shin C , Shin HD , Kimm K , Kim H‐L , Oh B , Park KS
Published: January 2009

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. Leptin inhibits the glucose‐stimulated insulin secretion, and leptin receptors are present on β cells as well as on fat cells, thus enabling leptin to modulate both insulin secretion and action. Therefore, leptin (LEP) and leptin receptor (LEPR) genes could play a role in the regulation of glucose and insulin after an oral glucose load. For the association study of LEP and LEPR with T2DM and metabolic traits, 752 women from Seoul National University Hospital (SNUH data) and 532 women from the Korean Health and Genome Study (KHGS data) were selected. Using the SNUH data, we identified that LEP−632G>A and +4998A>C polymorphisms were marginally associated with T2DM, LEP+4950G>A was significantly associated with several metabolic traits, and LEPR+5193G>A, +7187A>C, +27265G>A, +35861T>C, and +52289A>G showed strongly significant association with body mass index (BMI). We observed reproducibility of these results using the KHGS data; LEP+4950G>A and +4998A>C were significantly associated with systolic blood pressure and low‐density lipoprotein cholesterol level, respectively. In conclusion, we observed that several polymorphisms in LEPR that had previous reports of association with BMI were significantly replicated in our samples and newly found that some variations of LEP were associated with T2DM and metabolic traits.
Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations
Authors: Barrow E , Alduaij W , Robinson L , Shenton A , Clancy T , Lalloo F , Hill J , Evans DG
Published: January 2009

Hereditary non‐polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first‐degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan–Meier analysis. Three hundred and forty‐one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8–52.9). The cumulative risk in males was 54.3% (95% CI 50.7–57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8–49.9). These penetrance estimates from HNPCC families attending high‐risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high‐risk clinic. Current colonoscopic screening guidelines are appropriate.
X‐linked hypohidrotic ectodermal dysplasia. Genetic and dental findings in 67 Danish patients from 19 families
Authors: Lexner MO , Bardow A , Juncker I , Jensen LG , Almer L , Kreiborg S , Hertz JM
Published: January 2009

This study aimed to investigate genotype and phenotype in males affected with X‐linked hypohidrotic ectodermal dysplasia (HED) and in female carriers, to analyse a possible genotype–phenotype correlation, and to analyse a possible relation between severity of the symptoms and the X‐chromosome inactivation pattern in female carriers. The study group comprised 67 patients from 19 families (24 affected males and 43 female carriers). All participants had clinical signs of ectodermal dysplasia and a disease‐causing EDA mutation. The EDA gene was screened for mutations by single‐stranded conformational polymorphism and direct sequencing. Multiplex ligation‐dependent probe amplification (MLPA) analysis was used to detect deletions/duplications in female probands. Sixteen different EDA mutations were detected in the 19 families, nine not described previously. The MLPA analysis detected a deletion of exon 1 in one female proband. No genotype–phenotype correlations were observed, and female carriers did not exhibit a skewed X‐chromosome inactivation pattern. However, in two female carriers with pronounced clinical symptoms, in whom the parental origin of each allele was known, we observed that mainly the normal allele was inactivated.
Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function
Authors: Shariat N , Holladay CD , Cleary RK , Phillips JA , Patton JG
Published: January 2009

A heterozygous single base mutation in the human growth hormone (GH) gene (GH‐1) was identified in a family presenting with isolated GH deficiency type II (IGHD II). Affected individuals have a guanine to adenine transition at the first nucleotide of exon 3 (E3+1 G→A) that results in exon skipping and production of a dominant‐negative 17.5‐kDa isoform. We show that the mechanistic basis for exon skipping is due to the unique position of this mutation because it weakens the 3′ splice site and simultaneously disrupts a splicing enhancer located within the first seven bases of exon 3. A G→T mutation at this same position not only affects splicing but also results in a premature stop codon for those transcripts that include exon 3. Thus, mutations that alter the first nucleotide of exon 3 illustrate the various mechanisms by which changes in sequence can cause disease: splice site selection, splicing enhancer function, messenger RNA decay, missense mutations, and nonsense mutations. For IGHD II, only exon skipping leads to production of the dominant‐negative isoform, with increasing skipping correlating with increasing disease severity.
Predictive testing for Huntington disease in a developing country
Authors: Futter MJ , Heckmann JM , Greenberg LJ
Published: January 2009

Predictive testing for Huntington disease (HD), by means of direct mutation analysis, has been offered at the Division of Human Genetics, University of Cape Town, from 1995. The aim of this study was to compile a comprehensive profile of the participants who had undergone predictive testing in the Western Cape from 1995 to 2005. The sociodemographic data, uptake and outcome of tests were analyzed to inform changes to improve the current genetic counseling services. A retrospective cross‐sectional design using a ‘multi‐method’ approach of both qualitative and quantitative methods was used. Data were gathered from the participants’ hospital files and genetic database. Psychosocial data were obtained by face‐to‐face interviews with the participants in their homes or venues of choice. A total of 36 predictive tests were performed. The uptake for predictive testing was approximately 4.5% of the estimated at‐risk population. The cohort of 27 individuals comprised 16 females and 11 males. Their mean age was 35.3 years; 6 were mixed ancestry and 21 were White people (European ancestry); 11 tested gene positive, 15 gene negative and 1 was in the reduced penetrance range. The most important issue identified was that the uptake of individuals classified as mixed ancestry was substantially lower than that of the White people possibly due to limited access to the predictive testing program because of the low levels of income and education in the general population of families with HD. Strategies to address these aspects have been incorporated into the program and will be reassessed after 1 year.
RPGRIP1L mutations are mainly associated with the cerebello‐renal phenotype of Joubert syndrome‐related disorders
Authors: Brancati F , Travaglini L , Zablocka D , Boltshauser E , Accorsi P , Montagna G , Silhavy JL , Barrano G , Bertini E , Emma F , Rigoli L ,   The International JSRD Study Group, Dallapiccola B , Gleeson JG , Valente EM
Published: January 2009

Joubert syndrome‐related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the ‘molar tooth sign’ (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel–Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello‐renal presentation (∼12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello‐renal subgroup, while they overall represent a rare cause of JSRD (<2%).
Attitudes antecedent to transition to self‐management of a chronic genetic disorder
Authors: Giarelli E , Bernhardt BA , Pyeritz RE
Published: January 2009

Marfan syndrome (MFS) is the exemplar of chronic genetic disorders that require multiorgan system management by health care providers (HCPs) and lifelong self‐management by affected individuals. This article describes the ways to facilitate transition to self‐management (TSM) by the adolescent with MFS. This thematic content analysis uses data collected for a larger grounded theory investigation of TSM of a chronic genetic disorder in adolescents and focuses on the system issues related to transition. A total sample of 107 included three groups of participants: parents (n = 39), adolescents (n = 37, ages 14–21 years) and young adults (n = 16, ages 22–34 years) with MFS, and HCPs (n = 15), including physicians, genetic counselors, and nurses. Data were derived from 180 transcripts of audiotaped interviews and a sociodemographic survey. Frames of mind that are antecedent to transition were belief in the diagnosis, wanting to understand and appreciate the cause and effect of MFS, and willing to share responsibility in problem solving. These frames of mind occurred primarily within the context of the family relationship. Parents taught children self‐surveillance as ‘listening to one’s body’. The parent’s fears and need to stay involved in the child’s health care slowed the child’s independent work on self‐management responsibilities. A systematic, institutionalized transition program for adolescents might involve parents and the child soon after diagnosis and incrementally build acknowledgment, understanding, and rapport.
Depression during pregnancy: the potential impact of increased risk for fetal aneuploidy on maternal mood
Authors: Hippman C , Oberlander TF , Honer WG , Misri S , Austin JC
Published: January 2009

Depression during pregnancy can have serious consequences for families. Indications of fetal aneuploidy can induce maternal stress, a risk factor for depression. Few studies have assessed symptoms of depression in pregnant women soon after they receive results indicating increased risk for fetal aneuploidy. We compared symptoms of depression in women who had increased risks for fetal aneuploidy with two other groups of pregnant women at similar gestational ages: controls, and women taking antidepressant medications (MEDS). Eighty‐one women attending the British Columbia (BC) Medical Genetics (MG) Program regarding positive maternal serum screens or ultrasound soft marker findings completed the Edinburgh Postnatal Depression Scale (EPDS). Control (n = 41) and MEDS (n = 41) groups were recruited from the community or the BC Reproductive Mental Health program. A threshold score of 12 on the EPDS was used to calculate percentages of women likely to be depressed. Mean EPDS scores were compared using anova, followed by post‐hoc tests. In the control, MG, and MEDS groups, 2.4%, 35%, and 52.4% of women, respectively, scored above 12. Mean EPDS score was significantly higher in the MG group than in the control group (p < 0.0001). These results suggest a place for depression screening in prenatal genetic counseling.
Hope for treatment of nephronophthisis and related ciliopathies
Authors: Madan D
Published: January 2009

Loss of nephrocystin‐3 function can cause embryonic lethality, Meckel‐Gruber‐like syndrome, situs inversus, and renal‐hepatic‐pancreatic dysplasia Bergmann et al. (2008) The American Journal of Human Genetics 82: 959–970
Anderson’s disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities
Authors: Silvain M , Bligny D , Aparicio T , Laforêt P , Grodet A , Peretti N , Ménard D , Djouadi F , Jardel C , Bégué JM , Walker F , Schmitz J , Lachaux A , Aggerbeck LP , Samson‐Bouma ME
Published: January 2009

Anderson’s disease (AD) or chylomicron retention disease (CMRD) is a rare hereditary lipid malabsorption syndrome linked to SARA2 gene mutations. We report in this study a novel mutation in two sisters for which the Sar1b protein is predicted to be truncated by 32 amino acids at its carboxyl‐terminus. Because the SARA2 gene is also expressed in the muscle, heart, liver and placenta, extraintestinal clinical manifestations may exist. For the first time, we describe in this study in the two sisters muscular as well as cardiac abnormalities that could be related to the reported expression of SARA2 in these tissues. We also evaluated six other patients for potential manifestations of the SARA2 mutation. The creatine phosphokinase levels were increased in all patients [1.5–9.4 ×normal (N)] and transaminases were moderately elevated in five of the eight patients (1.2–2.6 × N), probably related to muscle disease rather than to liver dysfunction. A decreased ejection fraction occurred in one patient (40%, N: 60%). The muscle, liver and placental tissues that were examined had no specific abnormalities and, in particular, no lipid accumulation. These results suggest that myolysis and other extraintestinal abnormalities can occur in AD/CMRD and that the clinical evaluation of patients should reflect this.
Novel PTEN mutations in neurodevelopmental disorders and macrocephaly
Authors: Orrico A , Galli L , Buoni S , Orsi A , Vonella G , Sorrentino V
Published: January 2009

Somatic mutations of the phosphatase and tensin (PTEN) gene have been frequently detected in many types of human cancer. However, germline mutations can determine multiple hamartoma syndromes and, as more recently ascertained, syndromes clinically characterized by autism associated with macrocephaly. To determine whether germline mutations of PTEN may lead to different phenotypes, we screened all the nine exons of the PTEN gene in 40 patients with neurodevelopmental disorders, with or without features of autism spectrum disorder, associated with macrocephaly. Three novel de novo missense mutations were found (p.H118P, p.Y176C, p.N276S) in two severely mentally retarded patients with autism and in a subject with neurodevelopmental disorders without autistic features. Our results provide evidence that PTEN germline mutations may sustain a more wide phenotypical spectrum than previously suggested.
MicroRNA epigenetic alterations: predicting biomarkers and therapeutic targets in human diseases
Authors: Wang Y , Liang Y , Lu Q
Published: January 2009

MicroRNAs (miRNAs) consist of a class of evolutionarily conserved small non‐coding RNA that regulates target messenger RNAs by mechanisms such as incomplete base pairing and post‐transcriptional gene silencing. Recent studies have shown that aberrant miRNA expression is a common feature of many human disorders including aging, heart diseases, cancer, autoimmune diseases and others. It seems likely that miRNA expression levels can be used as novel diagnostic markers. MiRNAs may also provide a new strategy for therapeutic interventions. In this review, we focus on recent advances in understanding how miRNA changes contribute to disease development and their potential as novel biomarkers and therapeutic targets for human diseases.