ABSTRACT
Signs of skeletal dysplasias are relatively common in fetuses with abnormal ultrasound (US) findings. The diversity of congenital skeletal disorders, the possibility of late-onset severe phenotypes and overlapping syndromes can be a challenge in the way of diagnosis, even if prenatal high-throuput sequencing allows for a better diagnosis, prognosis and genetic counseling. Hajdu-Cheney spectrum pathologies are rarely described in prenatal, and the signs associated remain poorly known, and do not include specific postnatal signs as acro-osteolysis and premature osteoporosis. We hereby report a couple for whom a medical termination of pregnancy was performed because a severe polymalformative syndrome associating severely short limbs with bowed long bones, severe cardiopathy, hyperechogenic kidneys and dysmorphism. After fetopathological and radiological examinations, Exome Sequencing (ES) was performed and revealed a de novo truncating mutation in the last exon of NOTCH2, responsible for Hajdu-Cheney or Serpentine Fibula Polycystic Kidney syndromes.
Subject(s)
Acro-Osteolysis , Hajdu-Cheney Syndrome , Osteoporosis , Female , Humans , Pregnancy , Hajdu-Cheney Syndrome/diagnostic imaging , Hajdu-Cheney Syndrome/genetics , Osteoporosis/genetics , Acro-Osteolysis/genetics , Exons , Labor Presentation , Receptor, Notch2/geneticsABSTRACT
INTRODUCTION: The origin of polycythemia is often simple to detect. Sometimes it is necessary to look for hereditary forms, the decisive parameters being the dosage of erythropoietin and the measurement of the oxygen dissociation curve (P50). These rare diseases are related to high oxygen-affinity haemoglobins, abnormalities of the erythropoietin receptor or dysfunction of the HIF (hypoxia-inducible factor) pathway. CASE REPORT: We report the case of a 56-year-old patient with unexplained polycythemia associated with normal serum erythropoietin and normal P50, in whom the never previously described mutation c.400C>T(p.Gln134*) on exon 1 in the EGLN1 gene (encoding PHD2) was found. CONCLUSION: In the face of an unexplained polycythemia a good cooperation between clinicians and biologists is necessary to be able to characterize rare hereditary pathologies.
Subject(s)
Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Polycythemia/diagnosis , Polycythemia/genetics , Erythropoietin/blood , Family , Humans , Hypoxia/blood , Hypoxia/genetics , Male , Middle Aged , Mutation , Polycythemia/bloodSubject(s)
Cell Cycle Proteins/genetics , Contracture/genetics , Pulmonary Fibrosis/genetics , Sclerosis/complications , Skin Abnormalities/complications , Skin Diseases, Genetic/complications , Tendons/pathology , Adolescent , Adult , Atrophy/genetics , Atrophy/pathology , Child , Child, Preschool , Erythema/genetics , Erythema/pathology , Female , Follow-Up Studies , Humans , Infant , Lymphedema/genetics , Lymphedema/pathology , Male , Middle Aged , Mutation , Retrospective Studies , Sclerosis/genetics , Sclerosis/pathology , Skin/pathology , Skin Abnormalities/genetics , Skin Abnormalities/pathology , Skin Diseases, Genetic/genetics , Skin Diseases, Genetic/pathology , Young AdultABSTRACT
The FOXP1 gene, located on chromosome 3p13, encodes the Forkhead-box protein P1, one of the four forkhead transcription factors which repress transcription by forming active homo- and heterodimers and regulate distinct patterns of gene expression crucial for embryogenesis and normal development. FOXP1 mutations, mostly truncating, have been described in patients with mild to moderate intellectual disability (ID), autism spectrum disorder (ASD), and speech and language impairment (MIM #613670). Here, we report a small de novo heterozygous balanced inversion of 2.1â¯Mb located at 3p14.1p13 identified by Whole Genomic Sequencing (WGS) and disrupting the genes FAM19A4 and FOXP1. This inversion was found in a patient with severe ID, ASD, seizures and very unusual vascular anomalies which were never described in the clinical spectrum of FOXP1 mutations. We show that the neurodevelopmental phenotype observed in the patient most likely results from FOXP1 haploinsufficiency as this heterozygous inversion leads to a 60 to 85% decrease of FOXP1 mRNA levels and to the complete absence of FOXP1 full-length protein. These findings, in addition to expanding the molecular spectrum of FOXP1 mutations, emphasize the emerging role of WGS in identifying small balanced chromosomal rearrangements responsible for neurodevelopmental disorders and not detected by conventional cytogenetics.
Subject(s)
Forkhead Transcription Factors/genetics , Intellectual Disability/genetics , Repressor Proteins/genetics , Whole Genome Sequencing , Adult , Autism Spectrum Disorder , Female , Humans , Language Disorders , Mutation , RNA, Messenger/genetics , SeizuresABSTRACT
Bernard-Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x109/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets.
Subject(s)
Bernard-Soulier Syndrome/diagnosis , Bernard-Soulier Syndrome/genetics , Genetic Variation , Platelet Glycoprotein GPIb-IX Complex/genetics , Alleles , Bernard-Soulier Syndrome/blood , Biomarkers , Child, Preschool , Computational Biology/methods , Female , Genetic Association Studies , Genotype , Humans , Models, Molecular , Mutation , Phenotype , Platelet Glycoprotein GPIb-IX Complex/chemistry , Protein Conformation , Sequence Analysis, DNA , Structure-Activity RelationshipABSTRACT
Hereditary sensory and autonomic neuropathies (HSAN) type II are characterized by autosomal recessive inheritance, onset at birth and self-mutilating behavior. Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia. Whole-exome sequencing showed a homozygous frameshift variant c.[577_580del], p.(Lys193Phefs*37) in ARL6IP1. The protein harbors reticulon-like short hairpin transmembrane domains and has a role in endoplasmic reticulum shaping. The variant causes an additional C-terminus hydrophobic domain which could disrupt its function. ARL6IP1 interacts with atlastin-1 responsible for SPG3A and HSAN type ID. This report highlights the role of ARL6IP1 in the pathophysiology of insensitivity to pain and spastic paraplegia.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Genetic Predisposition to Disease/genetics , Hereditary Sensory and Autonomic Neuropathies/genetics , Membrane Proteins/genetics , Mutation , Pain Insensitivity, Congenital/genetics , Paraplegia/genetics , Amino Acid Sequence , Base Sequence , Child, Preschool , Female , Homozygote , Humans , Male , Pedigree , Exome Sequencing/methodsABSTRACT
BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.
Subject(s)
Breast Neoplasms/genetics , Genes, BRCA1 , Genes, BRCA2 , Genetic Predisposition to Disease/genetics , Mutation , Ovarian Neoplasms/genetics , Female , Humans , Middle AgedABSTRACT
BACKGROUND: In most laboratories, the severity of hemophilia A is assessed by the factor VIII activity (FVIII:C) one-stage assay. However, comparisons of these results with those of two-stage assays can reveal discrepancies and suggest misdiagnosis. PATIENTS/METHODS: In this monocentric study, we measured FVIII:C with two methods (one-stage chronometric and chromogenic assays) in 307 (173 families) patients with moderate/mild hemophilia A. To compare results, we used a chronometric/chromogenic ratio. Discrepancy was defined as a ratio < 0.5 or > 1.5. We studied their putative involvement at known FVIII functional sites, their interspecies conservation status, and their spatial position within the FVIII structure. RESULTS: Thirty-six patients from 17 families exhibited a discrepancy between the two assays: 12 (6.9%) families had a low ratio (< 0.5), and five (2.9%) families had a high ratio (> 1.5). Qualitative deficiency was diagnosed in about 16% of the families. Molecular studies were performed in 15 of these 17 families, resulting in each case in the identification of missense mutations, including three novel mutations. We were further able to propose a pathophysiologic explanation. CONCLUSIONS: In this monocentric study, we have demonstrated a discrepancy between FVIII:C assay results in 10% of families with moderate/mild hemophilia A. The prevalence of 'inverse' discrepancy (i.e. low chronometric/chromogenic ratio) is high as compared with previous reports. We suggest that both FVIII:C assays are recommended in patients with moderate/mild hemophilia A for a complete biological phenotype. This could also improve our knowledge of the FVIII structure-function relationships.
Subject(s)
Factor VIII/analysis , Hemophilia A/blood , Hemophilia A/genetics , Amino Acid Substitution , Blood Chemical Analysis/methods , Chromogenic Compounds , Conserved Sequence , DNA Mutational Analysis , Factor VIII/chemistry , Factor VIII/genetics , France/epidemiology , Genetic Association Studies , Hemophilia A/epidemiology , Humans , Male , Models, Molecular , Mutation, Missense , Protein Structure, TertiaryABSTRACT
Pre-axial polydactyly type II (PPDII, MIM #174500), Werner mesomelic syndrome (MIM %188770) and Haas polysyndactyly (MIM #186200) are a group of closely related conditions caused by mutations in a long-range Sonic hedgehog (SHH, MIM *600725) regulator called ZRS. To date, 19 point mutations, 10 duplications and 1 triplication of the ZRS associated with those pre-axial polydactylies have been reported in humans, mice, cats and chickens. Some of these have been shown to cause ectopic expression of Shh in the limb bud in mice, leading to a polydactylous phenotype, but the precise mechanism by which ZRS mutations generate this phenotype remains unknown. We present two PPDII families with fully penetrant point mutations in ultra-conserved predicted binding sites for transcription factors SOX9 and PAX3, two possible candidates for regulating SHH expression. Screening for point mutations or copy-number variation of the ZRS, high-resolution array-CGH, and screening of other conserved non-coding sequences (CNS) surrounding SHH in a third family are negative. This is the sixth PPDII pedigree with possible linkage to 7q36 that presents with no detectable ZRS mutation. We hypothesize that another nearby regulatory sequence, or an undetected position effect between ZRS and SHH, could be responsible for negative familial cases linked to 7q36.
Subject(s)
Genetic Predisposition to Disease/genetics , Hedgehog Proteins/genetics , Mutation , Polydactyly/genetics , Animals , Base Sequence , Binding Sites/genetics , DNA Mutational Analysis , Family Health , Humans , Molecular Sequence Data , PAX3 Transcription Factor , Paired Box Transcription Factors/genetics , Pedigree , Point Mutation , SOX9 Transcription Factor/genetics , Sequence Homology, Amino AcidABSTRACT
BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.
Subject(s)
Colorectal Neoplasms/genetics , DNA Glycosylases/genetics , Adult , Aged , Colorectal Neoplasms/etiology , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Mutation , Risk FactorsSubject(s)
Fragile X Syndrome/diagnosis , Prenatal Diagnosis/methods , Chorionic Villi Sampling , DNA Methylation , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , Humans , Male , Molecular Diagnostic Techniques/methods , Mutation , Polymerase Chain Reaction/methods , Pregnancy , Sensitivity and Specificity , Time Factors , Trinucleotide Repeat Expansion/geneticsABSTRACT
BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score Subject(s)
Cognition Disorders/genetics
, Fragile X Mental Retardation Protein/genetics
, Fragile X Syndrome/genetics
, Penetrance
, Alleles
, Blotting, Southern
, DNA/chemistry
, DNA/genetics
, Double-Blind Method
, Humans
, Male
, Middle Aged
, Neuropsychological Tests
, Trinucleotide Repeat Expansion/genetics
ABSTRACT
Molecular pharmacogenetic units have recently been established in several hospital laboratories in France. The clinical impact of these units is still limited and numerous problems of organizational, ethical, legal, technical, social and economical nature remain to be resolved. However, an increasing number of these units, a rise in their activities and an enlargement of their scope of application are foreseeable in the future. Ultimately, these units would significantly contribute to limit the public health problem caused by interindividual variabilities in drug effects. In view of these prospects, it seems essential that such hospital activity should be quickly recognised by the authorities and the various health sectors in France. It is also essential that the problems that arise from such pharmacogenetic activities should be considered by the authorities and would profit from the organization of a national network and from financial guarantees.
Subject(s)
Laboratories, Hospital/trends , Pharmacogenetics/trends , Drug-Related Side Effects and Adverse Reactions , France , Humans , Laboratories, Hospital/ethics , Laboratories, Hospital/statistics & numerical data , Methyltransferases/deficiency , Methyltransferases/genetics , Pharmacogenetics/ethics , Pharmacogenetics/statistics & numerical data , Public HealthABSTRACT
BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.
Subject(s)
Genes, BRCA2 , Germ-Line Mutation/genetics , Exons/genetics , Female , Humans , Middle Aged , Polymerase Chain Reaction , Sequence Deletion/geneticsSubject(s)
Germ-Line Mutation/genetics , Hyperparathyroidism/etiology , Multiple Endocrine Neoplasia Type 2a/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Female , Humans , Middle Aged , Pedigree , Proto-Oncogene Proteins c-retSubject(s)
Carcinoma, Medullary/genetics , Genetic Predisposition to Disease , Germ Cells , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Transfection , Base Sequence , DNA Primers , Humans , Proto-Oncogene Mas , Proto-Oncogene Proteins c-retABSTRACT
BACKGROUND: Cyclo-oxygenase-2 over-expression has been reported in most advanced human colorectal cancers. AIMS: To assess the prevalence of cyclo-oxygenase-2 over-expression in non-advanced colorectal cancers, to investigate the correlation between cyclo-oxygenase-2 status and tumour clinicopathological features and molecular phenotype, and to determine the impact of cyclo-oxygenase-2 status on long-term clinical outcome. METHODS: Sixty-one patients who had undergone surgery for colorectal cancer without lymph node involvement were evaluated retrospectively. Cyclo-oxygenase-2 expression was determined by immunohistochemistry. The tumour replication error phenotype was assessed by amplification of the two microsatellites, BAT-25 and BAT-26. RESULTS: Thirty-six tumours were classified as cyclo-oxygenase-2 positive and 25 as cyclo-oxygenase-2 negative. No correlation was found between cyclo-oxygenase-2 over-expression and clinicopathological features or molecular phenotype. Cyclo-oxygenase-2 over-expression was an independent predictor of a poor prognosis. Indeed, the relative risk of tumour recurrence or death for patients with cyclo-oxygenase-2-positive tumours was 2.13 times that of patients with cyclo-oxygenase-2-negative tumours (P=0.008; 95% confidence interval, 1.22-3.73). This difference remained significant when post-operative deaths were censored in the multivariate analysis (P=0.014). CONCLUSION: Cyclo-oxygenase-2 over-expression is not associated with tumour phenotype, but is indicative of a poorer clinical outcome in patients with non-advanced colorectal carcinoma.
Subject(s)
Colorectal Neoplasms/metabolism , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Aged , Cyclooxygenase 2 , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Humans , Immunohistochemistry/methods , Male , Membrane Proteins , Microsatellite Repeats , Neoplasm Recurrence, Local/metabolism , Phenotype , Prognosis , Regression Analysis , Retrospective Studies , Survival AnalysisABSTRACT
In many haematological diseases, and more particularly in B-cell chronic lymphocytic leukaemia (B-CLL), the existence of a tumour suppressor gene located within the frequently deleted region 13q14.3, has been put forward. A wide candidate region spanning from marker D13S273 to D13S25 has been proposed and an extensive physical map has been constructed by several teams. In this study, we sequenced a minimal core deleted region that we have previously defined and annotated it with flanking available public sequences. Our analysis shows that this region is gene-poor. Furthermore, our work allowed us to identify new alternative transcripts, spanning core regions, of the previously defined candidate genes DLEU1 and DLEU2. Since their putative involvement in B-CLL was controversial, our present study provide support for reconsidering the DLEU1 and DLEU2 genes as B-CLL candidate genes, with a new definition of their organisation and context.
Subject(s)
B-Lymphocytes/metabolism , Genes, Tumor Suppressor , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Sequence Deletion/genetics , Alternative Splicing/genetics , Base Sequence , Chromosome Mapping , Databases, Nucleic Acid , Exons/genetics , Expressed Sequence Tags , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Repetitive Sequences, Nucleic Acid/genetics , Sequence Analysis, DNAABSTRACT
Using allele-specific amplification method (ARMS), a highly sensitive one-stage allele-specific PCR, we have evaluated the incidence of NRAS and KRAS2 activating mutations (codons 12, 13, and 61) in 62 patients with either monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM), primary plasma-cell leukemia (P-PCL), and also in human myeloma cell lines (HMCL). NRAS and/or KRAS2 mutations were found in 54.5% of MM at diagnosis (but in 81% at the time of relapse), in 50% of P-PCL, and in 50% of 16 HMCL. In contrast, the occurrence of such mutations was very low in MGUS and indolent MM (12.50%). Of note, KRAS2 mutations were always more frequent than NRAS. The validity of the technique was assessed by direct sequencing of cell lines and of some patients. Multiple mutations found in two patients were confirmed by subcloning exon PCR amplification products, testing clones with our method, and sequencing them. Thus, these early mutations could play a major role in the oncogenesis of MM and P-PCL.