RESUMO
A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.
Assuntos
Polipose Adenomatosa do Colo , Predisposição Genética para Doença , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Polipose Adenomatosa do Colo/genética , Ubiquitina-Proteína Ligases/genética , Proteína Axina/genética , Neoplasias Colorretais/genética , Proteína Supressora de Tumor p53/genética , Idoso , Proteínas Serina-Treonina Quinases/genética , Proteínas de Ligação a DNA/genética , Desoxirribonuclease (Dímero de Pirimidina)RESUMO
Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, 1,4-alpha-glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.
Assuntos
Artrogripose , Doença de Depósito de Glicogênio Tipo IV , Doença de Depósito de Glicogênio , Recém-Nascido , Humanos , Feminino , Gravidez , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/patologia , Artrogripose/complicações , Artrogripose/patologia , Glicogênio , Músculo Esquelético/patologia , Atrofia Muscular/complicações , Atrofia Muscular/patologia , Doença de Depósito de Glicogênio/complicaçõesRESUMO
Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.
Assuntos
Aneuploidia , Transtornos Cromossômicos , Cromossomos Humanos Par 22 , Anormalidades do Olho , Cardiopatias Congênitas , Humanos , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/genéticaRESUMO
BACKGROUND AND PURPOSE: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. METHODS: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. RESULTS: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. CONCLUSIONS: This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.
Assuntos
Doença de Charcot-Marie-Tooth , Humanos , Suíça , Mutação , Doença de Charcot-Marie-Tooth/genética , Genótipo , Atrofia MuscularRESUMO
BACKGROUND: Three partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors. OBJECTIVE: To assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study. RESULTS: All three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively). CONCLUSION: Our results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Fatores de Risco , Genes BRCA2RESUMO
At night, the health executive ensures that the caregivers on duty in the departments can provide continuity of care under appropriate safety conditions for all. Involved in the functioning of the establishment, he/she collaborates with the director on duty and favours, when night situations require it, efficient decision making in compliance with the regulations. Lightening on the specific missions of this manager who, at night, works in confidence alongside the caregivers.
Assuntos
Continuidade da Assistência ao Paciente , Feminino , HumanosRESUMO
Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.
Assuntos
Opacidade da Córnea , Anormalidades do Olho , Segmento Anterior do Olho/anormalidades , Hibridização Genômica Comparativa , Opacidade da Córnea/diagnóstico , Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Variações do Número de Cópias de DNA/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Humanos , Mutação/genética , Fatores de Transcrição SOXB1/genéticaRESUMO
The POLD1 gene is involved in DNA proofreading to ensure accurate DNA replication. Some germline alterations in its exonuclease domain are associated with predisposition to cancers and colonic polyps. Only a few pathogenic variants have been clearly identified so far. Here we report a novel variant: c.1458G>T p.(Lys486Asn) that we classified as pathogenic, detected in two putatively unrelated families. The cancer spectrum was very similar to Lynch syndrome, implying an overlapped tissue susceptibility. The common presence of colonic polyps in carriers and the MMR proficient phenotype in tumors were distinctive features suggesting POLD1 implication. Some clinical characteristics observed in the carriers of this variant differed from those reported previously, suggesting a potential genotype/phenotype correlation, and very likely in relation to the functional importance of affected residues. Our findings provide further insight into understanding the role of POLD1 in cancer-related risk.
Assuntos
Pólipos do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Polimerase III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Diagnóstico Diferencial , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , FenótipoRESUMO
Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.
RESUMO
Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-ß4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-ß4 abundance was confirmed with ELISA. Knockout of thymosin-ß4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin ß4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.
Assuntos
Nefropatias , Sistema Urinário , Anormalidades Urogenitais , Líquido Amniótico , Animais , Criança , Feminino , Humanos , Rim/diagnóstico por imagem , Peptídeos , Gravidez , Estudos Prospectivos , Anormalidades Urogenitais/diagnóstico por imagem , Peixe-ZebraRESUMO
White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Assuntos
Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Variação Genética , Deficiência Intelectual/genética , Transtornos Neurocognitivos/genética , Transposases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Testes Neuropsicológicos , Fenótipo , Adulto JovemRESUMO
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Colo/anormalidades , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/genética , Proteínas do Tecido Nervoso/genética , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/patologia , Feto Abortado , Actinas/genética , Colo/patologia , Feminino , Homozigoto , Humanos , Recém-Nascido , Pseudo-Obstrução Intestinal/patologia , Masculino , Mutação/genética , Cadeias Pesadas de Miosina/genética , Cadeias Leves de Miosina/genética , Linhagem , Bexiga Urinária/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description. METHODS: We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae. RESULTS: Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1-28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series. CONCLUSIONS: Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/complicações , Neoplasias Cerebelares/genética , Meduloblastoma/genética , Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Criança , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Estudos Retrospectivos , beta Catenina/genéticaRESUMO
Lynch syndrome accounts for 3-5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.
Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Proteínas de Ligação a DNA/genética , Evolução Fatal , Humanos , Masculino , Mães , IrmãosRESUMO
Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Processamento Alternativo , Ciclo Celular , Linhagem Celular , Análise Mutacional de DNA , Estudos de Associação Genética/métodos , Genótipo , Humanos , Mutação , FenótipoRESUMO
OBJECTIVES: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. METHODS: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. RESULTS: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). CONCLUSION: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.
Assuntos
Testes Genéticos/métodos , Cardiopatias Congênitas/genética , Análise em Microsséries/métodos , Diagnóstico Pré-Natal/métodos , Adulto , Aberrações Cromossômicas , Cromossomos/química , Cromossomos/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Feto/química , Feto/metabolismo , França , Cardiopatias Congênitas/diagnóstico , Humanos , Cariotipagem , Gravidez , Estudos Retrospectivos , SíndromeRESUMO
BACKGROUND: Almost no prospective data on endoscopy in MUTYH monoallelic carriers are available. OBJECTIVE: This study aimed to define the prevalence of colorectal and duodenal adenomas in a population of people presenting with a single mutation of the MUTYH gene and being first-degree relatives of biallelic MUTYH mutation carriers. DESIGN: This study is a prospective cohort evaluation. PATIENTS: Patients were first-degree relatives of a patient who had polyposis with biallelic MUTYH mutation and carrying a single gene mutation of the gene from 12 French centers. SETTINGS: This is a multicenter study. INTERVENTION: Detailed data on life habits (tobacco, alcohol, and nonsteroidal anti-inflammatory drugs), extraintestinal manifestations, and germline analysis were recorded. Complete endoscopic evaluation (colonoscopy and upper endoscopy) with chromoendoscopy was performed. RESULTS: Sixty-two patients were prospectively included (34 women (55%), mean age of 54, range 30-70 years). Thirty-two patients (52%) presented with colorectal polyps at colonoscopy. Of these patients with polyps, 15 (25%) had only adenomas, 8 (13%) had only hyperplastic polyps, 1 (1%) had sessile serrated adenomas, and 8 (13%) had adenomas and/or sessile serrated adenomas. We detected, in total, 29 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 6 sessile serrated adenomas. Fourteen patients (23%) presented with a single adenoma, and 10 (16%) had 1 to 5 adenomas. No patient had more than 5 adenomas. At upper endoscopy, 3 had a limited number of fundic gland polyps; none had duodenal adenomas. The 2 main missense mutations c.1145G>A, p.Gly382Asp and c.494A>G, p.Tyr165Cys were associated with the development of colorectal adenomas/serrated polyps in these monoallelic carriers. LIMITATIONS: This study was limited by the small number of patients. CONCLUSIONS: This prospective study provides unique prospective data suggesting that monoallelic mutation carriers related to patients with polyposis show no colorectal polyposis and have very limited upper GI manifestations justifying an endoscopic follow-up. See Video Abstract at http://links.lww.com/DCR/A862.