Publications of François-Guillaume DEBRAY
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See detailMale and female hypogonadotropic hypogonadism associated with two novel non sense heterozygous mutations of Klotho beta gene (KLB)
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; PETIGNOT, Sandrine ULiege et al

Poster (2021, September 17)

Clinical Case 1: A 15-year-old boy, with congenital deafness of the right ear, without olfaction disorders, consults for pubertal and growth retardation (1.59m, 47kg). Bone age of 14 years, GH: 6.4 ng/ml ... [more ▼]

Clinical Case 1: A 15-year-old boy, with congenital deafness of the right ear, without olfaction disorders, consults for pubertal and growth retardation (1.59m, 47kg). Bone age of 14 years, GH: 6.4 ng/ml after ITT, LHRH-stimulateable gonadotropins, testosterone-total 99ng/dl (28-1110 ng/dl). Pituitary MRI is normal. His father and sister had late puberty around the age of 16. The patient treated with GH and Sustanon, reaches 1.77m and 79 kg. At the age of 16, suffering from MS, like his father. At 18 years, the gonadic balance is re-evaluated, normal (bilateral testicular volume: 14 ml). Clinical case 2: A 30 years old woman (1.62m, 61 kg) consults for secondary amenorrhea and infertility after clomiphene stimulation. She is normal weighted. After some left hypoesthesic symptomatology, a brain neuro inflammatory pathology was suspected on MRI (several frontal hyper intense T2 lesions) without a precise diagnosis. No pituitary lesions were identified. During follow up, a normal pregnancy was obtained. She delivered a 3.3 kg girl in 2019 . Genetic analysis: A panel of 61 genes of hypogonadotropic hypogonadism found in case 1 an heterozygous variant KLB c.3092T>A, p.(Leu1031*). This new variant (likely pathogenic, class IV), causes the appearance of a premature stop codon in exon 5 of the KLB gene. In case 2, a novel mutation c.2230_2231insGGTT, p.(Ala744Glyfs*45) was confirmed, causing a frame shift and stop codon (since codon Ala744).. Discussion: We describe two novel non sense KLB mutations and for the first time, a reproductive phenotype in a female affected patient. In our series of 54 consecutive patients with congenital hypogonadotropic hypogonadism sequenced with a panel of 61 candidate genes, KLB mutations represents 3.7% . This prevalence is in line with the 4% finding of Xu. et al(EMBO Mol Med 2017). In the series of XU et al, patients with missense KLB mutations had (n= 9/13) a metabolic syndrome too, unlike our patients, carrying a nonsense mutation. In mice, the loss of the klb gene leads to delayed puberty, impaired estrogenic cycle, subfertility. The association with multiple sclerosis/brain inflammatory lesions is intriguing, so other family members will be studied. [less ▲]

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See detailDiagnostic et suivi de la phénylcétonurie par LC-MS-MS au Maroc.
Meiouet, Faïza; Kabbaj, Saâd El; DEBRAY, François-Guillaume ULiege et al

in Annales de biologie clinique (2021)

Phenylketonuria is an inherited metabolic disease, of autosomal recessive transmission, due to the enzymatic deficit of phenylalanine hydroxylase, which transforms phenylalanine into tyrosine. The deficit ... [more ▼]

Phenylketonuria is an inherited metabolic disease, of autosomal recessive transmission, due to the enzymatic deficit of phenylalanine hydroxylase, which transforms phenylalanine into tyrosine. The deficit leads to an increase in phenylalanine and its metabolite, phenylpyruvic acid which is responsible for the toxicity and symptomatology characterized by serious neurological disorders. Through this work, we wanted to show: 1) the profile of phenylalanine concentrations in a cohort of 52 Moroccan phenylketonuric patients diagnosed in our laboratory by Tandem Mass Spectrometry coupled with HPLC; 2) The value of biological monitoring in the nutritional management of phenylketonuric patients. The results showed that phenylketonuria diagnosed in Morocco is characterized by a predominance of classic and moderate phenylketonuria in both sexes with a median concentration = 1,107 μmol/L, 26 times higher than that observed in the control group (median value = 42 μmol/L - p < 0.0001). The phenylalanine and tyrosine concentrations of 33 phenylketonuric patients regularly monitored by our laboratory highlights the effectiveness of the hypoproteic diet with a marked improvement in psychomotor development, a significant regression in behavioral disorders and an encouraging overall development of children. Conclusion: phenylketonuria is a disease that would be frequent in Morocco but it is still diagnosed at the stage of severe mental retardation. A better management of these patients could be considered when setting up a nation-wide neonatal screening program. [less ▲]

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See detailComment j'explore... un trouble du spectre de l'autisme
Barrea, Christophe ULiege; JADOT, Annick ULiege; DEBRAY, François-Guillaume ULiege et al

in Revue Médicale de Liège (2021), 76(10), 761-767

Le trouble du spectre de l’autisme (TSA) est une pathologie neurodéveloppementale complexe, caractérisée par des déficits de la communication et des interactions sociales associés à un caractère restreint ... [more ▼]

Le trouble du spectre de l’autisme (TSA) est une pathologie neurodéveloppementale complexe, caractérisée par des déficits de la communication et des interactions sociales associés à un caractère restreint et répétitif des comportements, des intérêts et des activités. Etant donné le caractère très hétérogène du trouble et l’absence de biomarqueur, son approche diagnostique doit être globale, multidisciplinaire, et répondre aux critères des classifications internationales. Par ailleurs, les TSA résultent d’un modèle multifactoriel dont l’étiologie demeure inconnue dans la majorité des cas. Afin d’optimiser le rendement exploratoire et d’homogénéiser les pratiques, ce document propose un cadre pour la mise au point des TSA en pédiatrie. [less ▲]

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See detailC2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.
Lausberg, Eva; Gießelmann, Sebastian; Dewulf, Joseph P. et al

in The Journal of clinical investigation (2021), 131(12),

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology ... [more ▼]

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology.METHODSWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTSWe identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism.CONCLUSIONSOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways. [less ▲]

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See detailComment j’explore… Une pathologie organique à l’origine d’un trouble pédopsychiatrique
BARREA, Christophe ULiege; DEBRAY, François-Guillaume ULiege; SIMON, Michaël ULiege et al

in Revue Médicale de Liège (2020), 75(1),

Psychiatric disorders in children may be the expression of underlying organic conditions. These are numerous and varied. The clinical presentation is often frustrating: psychiatric signs can remain ... [more ▼]

Psychiatric disorders in children may be the expression of underlying organic conditions. These are numerous and varied. The clinical presentation is often frustrating: psychiatric signs can remain isolated for years before other more specific organic signs appear. More recently, new treatments have been developed, making it possible to improve the prognosis of some of these organic diseases; screening them is therefore a daily concern for the child psychiatrist. This literature review discusses various paediatric treatable organic disorders that may have an isolated psychiatric presentation, to finally propose a decision tree algorithm based on somatic and psychiatric complaints reported. [less ▲]

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See detailComment j’explore… Un trouble du développement intellectuel chez l'enfant
BARREA, Christophe ULiege; LEROY, Patricia ULiege; DEBRAY, François-Guillaume ULiege et al

in Revue Médicale de Liège (2020), 75(10), 686-691

Global developmental delay (GDD) and intellectual development disorder (IDD) are common but heterogeneous pediatric conditions. Guided by a rigorous clinical and anamnestic examination, the diagnostic ... [more ▼]

Global developmental delay (GDD) and intellectual development disorder (IDD) are common but heterogeneous pediatric conditions. Guided by a rigorous clinical and anamnestic examination, the diagnostic approach is a dynamic process which is not limited to the intelligence quotient measurement. A large panel of paraclinical tests allows etiological exploration; this generally includes biological, genetic, metabolic and iconographic examinations. To maximize therapeutic efficiency and standardize practices, this document provides a guideline for the management of pediatric GDD/IDD. [less ▲]

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See detailGenetic and phenotypic spectrum associated with IFIH1 gain-of-function
Rice, Gillian I.; DEBRAY, François-Guillaume ULiege; HARVENGT, Julie ULiege et al

in Human Mutation (2020)

IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome ... [more ▼]

IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate. [less ▲]

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See detailActualités thérapeutiques dans les erreurs innées du métabolisme
Debray, François-Guillaume ULiege; WEEKERS, Laurent ULiege; Dadoumont, C. et al

in Revue Médicale de Liège (2020), 75(5-6), 420-425

Inborn errors of metabolism (IEM) represent a vast group of orphan genetic disorders associated with enzyme deficiencies, substrates accumulation and products depletion. For several decades, the ... [more ▼]

Inborn errors of metabolism (IEM) represent a vast group of orphan genetic disorders associated with enzyme deficiencies, substrates accumulation and products depletion. For several decades, the cornerstone of life-saving therapies in IEM was based on extreme manipulations of the nutritional intakes. Such outstanding dietary engineering is still relevant today, but new therapeutic avenues have emerged last years, based on better pathophysiological understanding and technological advances. In this paper, we summarize current and new therapeutic options in the field of IEM. [less ▲]

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See detailAvailability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network.
Heard, Jean-Michel; Vrinten, Charlotte; Schlander, Michael et al

in Orphanet journal of rare diseases (2020), 15(1), 3

BACKGROUND: The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases ... [more ▼]

BACKGROUND: The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. RESULTS: Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients' clinical status, characteristic, and personal choice. CONCLUSIONS: Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up. [less ▲]

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See detailKidney and vascular function in adult patients with hereditary fructose intolerance.
Simons, Nynke; Debray, François-Guillaume ULiege; Schaper, Nicolaas C. et al

in Molecular genetics and metabolism reports (2020), 23

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The ... [more ▼]

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m(2), p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study. [less ▲]

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See detailEfficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.
van Rijt, Willemijn J.; Jager, Emmalie A.; Allersma, Derk P. et al

in Genetics in medicine : official journal of the American College of Medical Genetics (2020), 22(5), 908-916

PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in ... [more ▼]

PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. METHODS: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. RESULTS: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). CONCLUSION: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients. [less ▲]

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See detailResearch activity and capability in the European reference network MetabERN
Heard, Jean-Michel; Bellettato, Cinzia; van Lingen, Corine et al

in Orphanet journal of rare diseases (2019), 14(1), 119

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 ... [more ▼]

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. RESULTS: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. CONCLUSIONS: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups. [less ▲]

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See detailDevelopmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations.
Cardenas-de-la-Parra, Alonso; Martin-Brevet, Sandra; Moreau, Clara et al

in NeuroImage (2019), 203

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants ... [more ▼]

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4-5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace. [less ▲]

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See detailPatients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content.
Simons, Nynke; DEBRAY, François-Guillaume ULiege; Schaper, Nicolaas C. et al

in Journal of Clinical Endocrinology and Metabolism (2019), 104(11), 5056-5064

CONTEXT: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic ... [more ▼]

CONTEXT: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. OBJECTIVE: To translate these experimental findings to the human situation. DESIGN: Case-control study. SETTING: Outpatient clinic for inborn errors of metabolism. PATIENTS OR OTHER PARTICIPANTS: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). MAIN OUTCOME MEASURE: IHTG content, assessed by proton magnetic resonance spectroscopy. RESULTS: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma beta-hydroxybutyrate, a biomarker of hepatic beta-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). CONCLUSIONS: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of beta-oxidation are involved in the pathogenesis. [less ▲]

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See detailEstimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice.
Jonch, Aia Elise; Douard, Elise; Moreau, Clara et al

in Journal of medical genetics (2019), 56(10), 701-710

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case ... [more ▼]

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders. METHODS: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. RESULTS: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias. CONCLUSIONS: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting. [less ▲]

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