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Objective Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL. Design We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors. Methods Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes. Results From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients. Conclusions This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported., SCOPUS: ar.j, info:eu-repo/semantics/published

Most pancreatic neuroendocrine neoplasms (pNEN) occur sporadically but they can also occur as part of multiple endocrine neoplasia type 1 (MEN1). MAX was originally described as an inherited pheochromocytoma-paraganglioma risk gene, but also has recently been implicated in pituitary tumorigenesis. Here we describe the first case of a pNEN associated with an inherited MAX gene deletion in a family with endocrine tumors. The patient was a male carrier of an intragenic exon 3 deletion inherited from his father who had recurrent pheochromocytomas and a macroprolactinoma. The patient underwent screening and hormonal studies but no pheochromocytoma-paraganglioma, pituitary or renal tumors were identified. However, abdominal magnetic resonance imaging (MRI) identified a 1 cm lesion in body of the pancreas. The lesion was hyperintense on T2-weighted signal, and there was hyperfixation of the tumor on 68Ga-DOTANOC PET-CT images. No biochemical evidence of pancreatic hormone excess was identified. Following a guided biopsy, a pathological diagnosis of a low grade pNEN was made and immunohistochemistry showed loss of MAX nuclear staining. Genetic analysis of the tumor tissue indicated copy number neutral loss of heterozygosity consistent with uniparental disomy. This is the first reported case of a MAX deletion associated pNEN and strengthens the argument that MAX may represent an inheritable multiple endocrine neoplasia risk gene. Further analysis of germline and somatic MAX mutations/deletions in large cohorts of unexplained NEN cases could help clarify the potential role of MAX in NEN etiology.

Approval was recently granted for a new treatment for spinal muscular atrophy (SMA). Given that the treatment is effective when administered early and the societal burden of SMA-related disability, the implementation of a newborn screening program is warranted. We describe the stepwise process that led us to launch a newborn screening program for SMA in Southern Belgium. Different political, ethical, and clinical partners were informed about this project and were involved in its governance, as were genetic and screening labs. We developed and validated a newborn screening method to specifically recognize homozygous deletions of exon 7 in the SMN1 gene. Subsequently, a 3-year pilot study has been recently initiated in one Belgian neonatal screening laboratory to cover 17.000 neonates per year. Coverage extension to all of Southern Belgium to screen 55.000 babies each year is underway. (C) 2019 Elsevier B.V. All rights reserved.

Background Participation in quality controls, also called external quality assessment (EQA) schemes, is required for the ISO15189 accreditation of the Medical Centers of Human Genetics. However, directives on the minimal frequency of participation in genetic quality control schemes are lacking or too heterogeneous, with a possible impact on health care quality. Objective The aim of this project is to develop Belgian guidelines on the frequency of participation in quality controls for genetic testing in the context of rare diseases. Methods A group of experts analyzed 90 EQA schemes offered by accredited providers and focused on analyses used for the diagnosis of rare diseases. On that basis, the experts developed practical recommendations about the minimal frequencies of participation of the Medical Centers of Human Genetics in quality controls and how to deal with poor performances and change management. These guidelines were submitted to the Belgian Accreditation Body and then reviewed and approved by the Belgian College of Human Genetics and Rare Diseases and by the National Institute for Health and Disability Insurance. Results The guidelines offer a decisional algorithm for the minimal frequency of participation in human genetics EQA schemes. This algorithm has been developed taking into account the scopes of the EQA schemes, the levels of experience, and the annual volumes of the Centers of Human Genetics in the performance of the tests considered. They include three key principles: (1) the recommended annual assessment of all genetic techniques and technological platforms, if possible through EQAs covering the technique, genotyping, and clinical interpretation; (2) the triennial assessment of the genotyping and interpretation of specific germline mutations and pharmacogenomics analyses; and (3) the documentation of actions undertaken in the case of poor performances and the participation to quality control the following year. The use of a Bayesian statistical model has been proposed to help the Centers of Human Genetics to determine the theoretical number of tests that should be annually performed to achieve a certain threshold of performance (eg, a maximal error rate of 1%). Besides, the guidelines insist on the role and responsibility of the national public health authorities in the follow-up of the quality of analyses performed by the Medical Centers of Human Genetics and in demonstrating the cost-effectiveness and rationalization of participation frequency in these quality controls. Conclusions These guidelines have been developed based on the analysis of a large panel of EQA schemes and data collected from the Belgian Medical Centers of Human Genetics. They are applicable to other countries and will facilitate and improve the quality management and financing systems of the Medical Centers of Human Genetics.

BACKGROUND Participation in quality controls, also called external quality assessment (EQA) schemes, is required for the ISO15189 accreditation of the Medical Centers of Human Genetics. However, directives on the minimal frequency of participation in genetic quality control schemes are lacking or too heterogeneous, with a possible impact on health care quality. OBJECTIVE The aim of this project is to develop Belgian guidelines on the frequency of participation in quality controls for genetic testing in the context of rare diseases. METHODS A group of experts analyzed 90 EQA schemes offered by accredited providers and focused on analyses used for the diagnosis of rare diseases. On that basis, the experts developed practical recommendations about the minimal frequencies of participation of the Medical Centers of Human Genetics in quality controls and how to deal with poor performances and change management. These guidelines were submitted to the Belgian Accreditation Body and then reviewed and approved by the Belgian College of Human Genetics and Rare Diseases and by the National Institute for Health and Disability Insurance. RESULTS The guidelines offer a decisional algorithm for the minimal frequency of participation in human genetics EQA schemes. This algorithm has been developed taking into account the scopes of the EQA schemes, the levels of experience, and the annual volumes of the Centers of Human Genetics in the performance of the tests considered. They include three key principles: (1) the recommended annual assessment of all genetic techniques and technological platforms, if possible through EQAs covering the technique, genotyping, and clinical interpretation; (2) the triennial assessment of the genotyping and interpretation of specific germline mutations and pharmacogenomics analyses; and (3) the documentation of actions undertaken in the case of poor performances and the participation to quality control the following year. The use of a Bayesian statistical model has been proposed to help the Centers of Human Genetics to determine the theoretical number of tests that should be annually performed to achieve a certain threshold of performance (eg, a maximal error rate of 1%). Besides, the guidelines insist on the role and responsibility of the national public health authorities in the follow-up of the quality of analyses performed by the Medical Centers of Human Genetics and in demonstrating the cost-effectiveness and rationalization of participation frequency in these quality controls. CONCLUSIONS These guidelines have been developed based on the analysis of a large panel of EQA schemes and data collected from the Belgian Medical Centers of Human Genetics. They are applicable to other countries and will facilitate and improve the quality management and financing systems of the Medical Centers of Human Genetics.

We share the concerns of Schorlin et al.1 on the SMN2 copy number quantification. In the context of newborn screening, SMN2 copy number is the main deciding factor for treatment.2,3

Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters.

Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val(158)Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus.

The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole-exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient’s disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding “next-generation” NBS.

Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in six Rwandan patients presenting a phenotype of Duchenne and Becker muscular dystrophies and six asymptomatic female carrier relatives using multiplex ligation-dependent probe amplification (MLPA). Our results revealed deletion of the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two brothers and a de novo deletion of the exons 46-50 in the fourth patient. No copy number variation was found in two patients. Only one female carrier presented exon deletion in the DMD gene. This is the first cohort of genetic analysis in Rwandan patients affected by Duchenne and Becker muscular dystrophies. This report confirmed that MLPA assay can be easily implemented in low-income countries.

Asthma is a heterogeneous disorder hallmarked by chronic inflammation in the respiratory system. Exacerbations of asthma are correlated with respiratory infections. Considering the implication of interferon regulatory factor 5 (IRF5) in innate and adaptive immunity, we investigated the preferential transmission patterns of ten IRF5 gene polymorphisms in two asthmatic family cohorts. A common IRF5 haplotype was found to be associated with asthma and the severity of asthmatic symptoms. Stratified analysis of subgroups of asthmatic individuals revealed that the associations were more pronounced in nonatopic asthmatic individuals. In addition, the risk alleles of IRF5 polymorphisms for asthma were almost completely opposite to those for autoimmune disorders. Our study provides the first evidence of association between IRF5 and asthma, and sheds light on the related but potentially distinct roles of IRF5 alleles in the pathogenesis of asthma and autoimmune disorders. (c) 2012 Elsevier B.V. All rights reserved.

Objectifs L’hypogonadisme hypogonadotrope congenital (HHC) est un syndrome pouvant combiner des anomalies reproductives et cerebrales. Nous presentons une etude multicentrique belge chez 56 patients avec HCC afin de preciser les aspects genetiques et cerebraux. Methodes La serie est etudiee avec un panel de 16 genes associes a HHC, incluant KAL1, FGFR1, PROKR2, PROK2, CHD7, FGF8, KISS1, KISS1R, TAC3, TACR3, GNRHR, GNRH1, NELF, WDR11, HS6ST1, SEMA3A, par NSG (MiSeq®, Illumina) et par sequencage direct (xGenLockdown Probes [IDT]). Une IRM cerebrale est realisee chaque fois que possible. Resultats La cohorte comprend 56 patients (48H/8F) appartenant a 47 familles. Nous avons identifie par olfactometrie 49 nIHH et 9 KS. Nous avons objective 14 nouveaux variants (class3 a 5) dans les genes suivants : TAC3 : (c.238+1G>A, c.170C>T-TACR3 : c.568C>G) FGFR1 : c.169C>A, c.937-1234C>T, c.2292+3A>G, c.1663+1G>A, c.1025T>A, c.1664-2A>T-CDH7 : c.7212_7214del, c.5261_5263del, c.7357A>-KISS1R : (c.502G>A, KISSR delete). Sur 32 patients avec RMN, l’imagerie n’etait pas contributive chez 21, mais 11 patients presentaient : malformation de Chiari type 1 (CM1) (n = 3), hypoplasie hypophysaire anterieure (n = 3), Kyste de Rathke (n = 1), dysplasie septo-optique (n = 2), hydrocephalie (n = 1) et kyste arachnoidien (n = 1). Conclusions Les patients avec HHC peuvent presenter des anomalies neurodeveloppementales, qu’il faut rechercher activement par imagerie. L’association syndromique de HHC et CM1 est intrigante : nous rapportons deux cas associes a une mutation FGFR1 (dont une non decrite). Nous decrivons, pour la premiere fois, 14 nouveaux variants associes a HHC incluant les genes : TAC3 TACR3, FGFR1 CDH7 et KISS1R.

Introduction CHD7 est un gene codant pour une helicase impliquee dans le remodeling de la chromatine. Des mutations monoalleliques ont ete identifiees chez des patients avec le syndrome polymalformatif de CHARGE. Plus recemment, certains patients pouvant present un hypogonadisme central avec ou sans anosmie ont ete decrits avec des mutations CHD7. CAS 1 : homme anosmique qui consulte a 16 ans pour retard pubertaire i (testiculaires de 5 mL). Testosterone Analyse genetiques par sequencage haut debit, des genes : KAL1, FGFR1, PROKR2, PROK2, CHD7, FGF8, KISS1, KISS1R, TAC3, TACR3, GNRHR, GNRH1, NELF, WDR11, HS6ST1, SEMA3A. Caryotype XY (2 patient) et XX (1 patient) normaux. Nous identifions quatre nouvelles mutations heterozygotes : Ex24 : c.5261_5263delGAG, p.Gly1754-Asp1755delinsAsp (entrainant la perte de Gly1754), Ex34 :c.7357A>G, p.Ser2453Gly, EX34 : c.7212_7214delGAG, c.3127G>A, p.Val1043Met. Conclusions CHD7 peut etre implique dans l’hypogonadisme hypogonadotrope avec ou sans anosmie, sans autres malformations telles que decrites dans le syndrome de CHARGE. Nous decrivons 4 mutations CHD7, dont trois non decrites et pathogenes d’apres les outils in silico.

Introduction CHD7 (locus 8q12.2), code pour une proteine transcriptionnelle Chromodomain Helicase DNA binding (CHD). Les mutations heterozygotes de CHD7 sont associees au syndrome de CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness), avec une prevalence de 1/10 000 naissances. Cas clinique Un garcon consulte a l’âge de 14 ans pour retard pubertaire. Il presente une anosmie. Il n’a pas de dysmorphie craniofaciale, ni palais ogival, ni des syncinesies. Une echographie renale et une IRM hypophysaire sont normales. La biologie demontre : testosterone 0,21 μg/L, LH 1,4 U/L, FSH 1,2 U/L. Les gonadotrophines sont stimulables par LHRH. Traite par Sustanon 250/mois, il atteint une taille adulte et des caracteres sexuels secondaires normaux. Sa mere est anosmique et a eu une menarche tardive. Les deux premieres de ses six grossesses ont necessite une stimulation ovarienne. Par sequenceur d’ADN a haut debit, nous recherchons une mutation de : KAL1, FGFR1, PROKR2, PROK2, CHD7, FGF8, KISS1, KISS1R, TAC3, TACR3, GNRHR, GNRH1, NELF, WDR11, HS6ST1, SEMA3A, en identifiant deux nouvelles mutations heterozygotes CHD7. La premiere : c.5261_5263del, p.Gly1754del, entraine la perte du residu Gly1754. La deuxieme est : c.7357A>G, p.Ser2453Gly. La signification fonctionnelle de ces mutations n’est pas connue. Elles se trouvent dans une region tres conservee, classee comme pathogene selon l’outil de prediction in silico Mutation Taster. Conclusions Le phenotype de ce patient est une forme probablement familiale et atypique de CHARGE. Nous avons identifie deux nouvelles mutations de CHD7 chez un patient avec un syndrome de Kallmann.

Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val(158)Met) has received increasing attention as a possible modulator of executive functioning and its neural correlates. However, this attention has generally centered on the prefrontal cortices because of the well-known direct impact of COMT enzyme on these cerebral regions. In this study, we were interested in the modulating effect of COMT genotype on anterior and posterior brain areas underlying interference resolution during a Stroop task. More specifically, we were interested in the functional connectivity between the right inferior frontal operculum (IFop), an area frequently associated with inhibitory efficiency, and posterior brain regions involved in reading/naming processes (the 2 main non-executive determinants of the Stroop effect). The Stroop task was administered during functional magnetic resonance imaging scanning to 3 groups of 15 young adults divided according to their COMT Val(158)Met genotype [Val/Val (VV), Val/Met (VM), and Met/Met (MM)]. Results indicate greater activity in the right IFop and the left middle temporal gyrus in homozygous VV individuals than in Met allele carriers. In addition, the VV group exhibited stronger positive functional connectivity between these 2 brain regions and stronger negative connectivity between the right IFop and left lingual gyrus. These results confirm the impact of COMT genotype on frontal functions. They also strongly suggest that differences in frontal activity influence posterior brain regions related to a non-executive component of the task. Particularly, changes in functional connectivity between anterior and posterior brain areas might correspond to compensatory processes for performing the task efficiently when the available dopamine level is low.

We describe a child with facial dysmorphism (trigonocephaly, epicanthus, upturned nose, small ears), thumb hypoplasia, micropenis, jejunal atresia and moderate mental retardation with dysphasia. Cytogenetic workup revealed high spontaneous level of chromosomal aberrations (without specific pattern and no quadriradial figures) and borderline to absent hypersensitivity to mitomycin C, making a diagnosis of Fanconi anemia unlikely. The child described here shares similarities with a small number of previous reports. We suggest to refer to this entity as episphalosomic syndrome. Episphalosomic syndrome shows some clinical overlap with Fanconi anemia, but lacks its cytogenetic hallmark. The hematological complications of Fanconi anemia have not been reported in this entity.

Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin's activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture.

Memories are consolidated during sleep by two apparently antagonistic processes: (1) reinforcement of memory-specific cortical interactions and (2) homeostatic reduction in synaptic efficiency. Using fMRI, we assessed whether episodic memories are processed during sleep by either or both mechanisms, by comparing recollection before and after sleep. We probed whether LTP influences these processes by contrasting two groups of individuals prospectively recruited based on BDNF rs6265 (Val66Met) polymorphism. Between immediate retrieval and delayed testing scheduled after sleep, responses to recollection increased significantly more in Val/Val individuals than in Met carriers in parietal and occipital areas not previously engaged in retrieval, consistent with “systems-level consolidation.” Responses also increased differentially between allelic groups in regions already activated before sleep but only in proportion to slow oscillation power, in keeping with “synaptic downscaling.” Episodic memories seem processed at both synaptic and systemic levels during sleep by mechanisms involving LTP.

Introduction Genetic variability related to the catechol-O-methyltransferase (COMT) gene (Val 158 Met polymorphism) has received increasing attention as a possible modulator of cognitive control functions. Methods In an event-related functional magnetic resonance imaging (fMRI) study, a modified version of the Stroop task was administered to three groups of 15 young adults according to their COMT Val 158 Met genotype [Val/Val (VV), Val/Met (VM) and Met/Met (MM)]. Based on the theory of dual mechanisms of control ( Braver et al., 2007 ), the Stroop task has been built to induce proactive or reactive control processes according to the task context. Results Behavioral results did not show any significant group differences for reaction times but Val allele carriers individuals are less accurate in the processing of incongruent items. fMRI results revealed that proactive control is specifically associated with increased activity in the anterior cingulate cortex (ACC) in carriers of the Met allele, while increased activity is observed in the middle frontal gyrus (MFG) in carriers of the Val allele. Conclusion These observations, in keeping with a higher cortical dopamine level in MM individuals, support the hypothesis of a COMT Val 158 Met genotype modulation of the brain regions underlying proactive control, especially in frontal areas as suggested by Braver et al.

Objectifs Etudier les phenotypes cliniques, genetiques et les reponses therapeutiques dans une serie de 34 patients liegeois avec hypogonadisme hypogonadotrope et normosmie (nIHH)/hyposmie (KS). Methodes L’etude des genes KAL1 (anosmine) et FGFR1 , est realisee dans notre centre depuis 2013. Dernierement, une analyse par panel est disponible pour les genes : KAL1 , FGFR1 , PROKR2 , PROK2 , CHD7 , FGF8 , KISS1 , KISS1R , TAC3 , TACR3 , GNRHR , GNRH1 , NELF , WDR11 , HS6ST1 , SEMA3A . Resultats La cohorte comprend 34 patients (31H/3F, 18 ± 9 ans) appartenant a 30 familles. Nous avons identifie par olfactometrie 25 nIHH et 8 KS. Deux patients avaient une malformation de Chiari I, deux patients presentaient une selle turcique partiellement vide, un kyste de la poche de Rathke et une fente palatine. L’analyse preliminaire a permis de mettre en evidence une mutation FGFR1 chez trois patients et une famille. Les mutations identifiees sont : c.1663 + 1G > A, c.1025T > A (p.Leu342*) et c.937-1234C > T (non repertoriee, exon 8a de l’isoforme IIIb). Un autre patient avait une mutation non repertoriee TAC3 c.238 + 1G > A. Une oligospermie a ete obtenue chez 6/12 hommes traites par hCG et FSH. Le traitement a permis un developpement des caracteres sexuels secondaires chez tous les patients. Le patient avec FGFR1 :c.937-1234C > T a eu une reversibilite spontanee de son hypogonadisme, apres 4 ans de traitement. Conclusions Les patients avec nIHH porteurs d’une mutation FGFR1 peuvent avoir des anomalies neuro developpementales, qu’il faut rechercher. L’association de nIHH et d’une malformation de Chiari est intrigante, rapportee seulement une fois dans la litterature (Kulmar & al. Pituitary 2010). Nous demontrons dans un cas de FGFR1 mute une reversibilite de l’hypogonadisme. Nous rapportons, enfin, deux nouvelles mutations TAC3 et FGFR1 .

Introduction La disruption du gene FGFR1 est liee a un phenotype variable d’hypogonadisme et troubles de l’olfaction. Observation Un jeune homme d’origine turque (1,88 m, 77 kg, 1,89 m d’envergure), issu d’une consanguinite entre cousins eloignes consulte a l’âge de 17 ans pour un retard pubertaire. Il a des testicules de 10 mL a gauche et 6 mL a droite, une verge de 5 cm. La testosterone totale est de 0,6 ng/mL (2–9 ng/mL). La LHRH stimule la LH de 1,3 a 9 mUI/L et la FSH de 0,9 a 2 mUI/L sans lesion hypophysaire a l’IRM. Il a une anosmie severe (sniff test 2/12) et une osteoporose lombaire et femorale. KAL-1 n’est pas mute. Il est traite par sustanon 250 IM/mois et reevalue sans traitement huit ans plus tard. L’examen testiculaire montre cette fois-ci deux testicules de 16 mL chacun et une verge de 12 cm. La testosterone est a 4,23 μg/L, la LH 4,4 UI/L et la FSH 2,5 mUI/L. Une analyse etendue du gene FGFR1 a identifie la mutation c.937C>T, p.His314Tyr a l’etat heterozygote, dans l’exon 8a, de l’isoforme IIIb, de FGFR1 . La signification fonctionnelle de cette mutation n’est pas connue. Situee dans une region tres conservee, elle est classee comme pathogene selon l’outil de prediction in silico Mutation Taster. Conclusions Nous decrivons une nouvelle mutation FGFR1 associee a un phenotype d’hypogonadisme hypogonadotrope reversible. Nous montrons egalement l’utilite d’une approche de recherche etendue aux formes alternativement epissees du gene FGFR1 dans cette pathologie complexe.

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. © 2012 by The American Society of Human Genetics. All rights reserved.

Polymorphisms in the region of the interleukin-28B (IL28B) gene have recently been associated with spontaneous and treatment induced clearance of hepatitis C virus infection. The specific mechanisms of how IL28B polymorphisms affect HCV suppression remain unknown. It is a matter of ongoing debate how to incorporate the IL28B data into the current treatment algorithms with pegylated interferon-alpha and ribavirin. The eventual role of the IL28B genotype in new therapeutic regimes with direct antiviral agents needs to be explored in the ongoing and future clinical studies with these agents.

The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune responses. The IRF5 gene has been shown to be associated with systemic lupus erythematosus and rheumatoid arthritis. We studied whether the IRF5 gene is also associated with inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC) and 241 controls from Wallonia, Belgium. The same polymorphisms were genotyped in a confirmatory cohort of 311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with IBD was observed for a 5 bp indel (CGGGG) polymorphism in the promoter region of the IRF5 gene. The association was detectable also in CD patients (P = 6.8 x 10(-4)) and was particularly strong among the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The association of the CGGGG indel was confirmed in the second cohort [P = 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG unit is predicted to create an additional binding site for the transcription factor SP1. Using an electrophoretic mobility shift assay, we show allele-specific differences in protein binding to this repetitive DNA-stretch, which suggest a potential function role for the CGGGG indel.

Introduction Les mutations du syndrome de Kallmann liees au gene FGFR1 ( fibroblast growth factor receptor 1 ) suivent une forme de transmission autosomique dominante. Patients et methodes Le cas index (JW) a un phenotype eunuchoide (Taille 1,93 m poids 90 kg, envergure 2,03 m) avec hypertelorisme et sans anosmie. A l’âge de 20 ans, les testicules ont un volume entre 5 et 6 mL. Le bilan gonadique demontre : testosterone : 0,38 μg/L (2,5–9), LH : 1,6 stimulable a 9,5 et FSH : 0,9 stimulable a 1,7 mUI/L apres LHRH, inhibine B : 182 ng/L (105–439). Sa sœur (LW) est diagnostiquee a 18 ans d’une amenorrhee primaire, le test LHRH montre une stimulation faible, l’œstradiol est effondre. Leur pere (HW) a presente un retard pubertaire traite par androgenes et a pu par la suite engendrer JW et LW sans autre traitement complementaire. On a identifie egalement une sœur de HW qui a un hypogonadisme et une sterilite primaire. Chez 3 cas (JW, LW, HW) nous avons pu identifier une mutation heterozygote FGFR1 c.1664-2A > T encore non repertoriee. Elle implique le site accepteur d’epissage de l’intron 12 de FGFR1, avec une probabilite importante d’un saut de l’exon 13. Pere et fille sont egalement porteurs d’une deuxieme mutation GNRHR heterozygote p.Gln106Arg. Conclusions Nous rapportons le phenotype et le genotype d’une nouvelle famille avec HH normosmique. La seule mutation du gene FGFR1 est probablement responsable du phenotype d’hypogonadisme, puisque la mutation GHRHR n’est pas presente chez le cas index.

Infliximab, a chimeric anti-tumour necrosis factor (TNF)-alpha antibody induces a clinical response in 70% of Crohn's disease patients and the response to infliximab therapy could be partially determined by genetic factors. The implication of both transmembrane and soluble forms of the TNF-alpha in the mechanism of action of infliximab has been demonstrated. The aim of our work was first to perform a complete study of TNF variants role in the response to infliximab in Crohn's disease. Secondly, considering the role of ADAM 17 in TNF-alpha shedding, the ADAM 17 locus was also studied. The response to infliximab was evaluated in 222 Caucasian Crohn's disease patients with a luminal (n=160) or fistulizing (n=62) form of the disease. Clinical and biological response evaluation was based on the Crohn's Disease Activity Index score and C-reactive protein level evolutions, respectively. The entire TNF gene was sequenced on the complete cohort. Twelve single nucleotide polymorphisms spanning the ADAM 17 locus were studied and haplotypes rebuilt. A clinical response was observed in 64% of the patients and biological response in 77.1% of patients. No association was found between the TNF gene and the response to infliximab. One haplotype in the ADAM 17 region was associated with a clinical response to infliximab in CD patients (adjusted P=0.045). In conclusion, our results exclude, with a reasonable power, an implication of the TNF gene in the response to infliximab in Crohn's disease, but reveal a potential role of the ADAM 17 gene in this response.

A haplotype in the lymphotoxin alpha (LTA) gene has been associated with a lack of response to infliximab in a small cohort of Crohn's disease (CD) patients. The present study aimed to confirm the implication of this haplotype in the response to infliximab in a larger cohort of Caucasian patients. The response to the first infusion with infliximab was evaluated in 214 Caucasian patients with either luminal (n=150) or fistulising (n=64) CD. Clinical response was based on the decrease in CD Activity Index (luminal) or on the evolution in the fistula discharge (fistulising). Biological response was assessed in 139 patients who had elevated C-reactive protein (CRP) before treatment and for whom CRP values were also available after treatment. A positive biological response was defined as a decrease in CRP of at least 25%. The patients were genotyped for six polymorphisms in the LTA gene. A positive clinical response was present in 65.4% of the patients and a positive biological response was observed in 80.6% of the patients. No association was found with any of the studied polymorphisms, nor with the previously published LTA haplotype and the response to infliximab. We could not confirm an association between the LTA locus and clinical or biological response to infliximab in a large cohort of CD patients.

Introduction Les FNMTC incluent deux ou plusieurs tumeurs au sein d’une meme famille. Une trentaine de familles ont ete etudiees jusqu’a present, incluant des formes papillaires avec (Ch19p13.2) ou sans oxyphilie (Ch2q21), en association avec un goitre multinodulaire (14q32), ou avec un cancer renal (Ch1q21). Materiels et methodes Nous disposons des donnees cliniques et genetiques issues de 8 familles liegeoises avec FNMTC. Aucune des familles n’a un phenotype suggerant les syndromes de Garner, Cowden, Werner ou de Carney. Une famille presente 5 cas avec un cancer papillaire opere, dans un contexte de goitre et thyroidite (la mere et ses 4 filles). Les 7 autres familles ont au moins deux cas avec un cancer thyroidien dans un contexte de goitre nodulaire. Resultats Dans les trois familles avec deux generations (parents-enfants), les enfants sont diagnostiques plus tot (36 vs 58 ans). Au total, 20 patients ont ete operes d’un cancer thyroidien (17F/3H). L’anatomopathologie retrouve majoritairement des cancers papillaires (13 micro/7 macro) sans oxyphilie. Trois microcancers sont multifocaux. Une premiere etude par CGH (comparative genomic hybridation) dans les leucocytes des patients de la plus grande famille n’a pas identifie de perte ou de gain de genes FNMTC specifiques. Le sequencage de l’exome sur ADN germinal est en cours dans les 2 plus grandes familles. Discussion Bien que rares, ces familles representent une possibilite exceptionnelle d’ approfondir notre comprehension sur la tumorigenese des neoplasies thyroidiennes. L’ identification de genes candidats participant a leur developpement pourra servir egalement comme cible therapeutique.

In South Belgium (Wallonia), the 'triple test' was introduced in 1990-1991, and is nowadays a widely accepted screening method for assessment of trisomy 21 risk in pregnancy. The 'triple test' is not regulated and can be freely performed by any biomedical lab, making epidemiological data unavailable. By contrast, cytogenetic investigations are limited to a few genetic centres, and accurate statistics can be easily built from their files. During the period 1984-1989, a total of 244 trisomy 21 (1/876 pregnancies) were diagnosed in the Genetic Centres of Liège and Loverval, 42 (17%) of them prenatally. During the period 1993-1998, 294 trisomy 21 (1/704 pregnancies) were observed, 165 (56%) of which prenatally, and more than 90% of affected pregnancies were terminated. Even after correction for late foetal loss of trisomic foetuses, the difference is highly significant, and corresponds to a theoretical shift in the incidence of trisomy 21 at birth from 1/794 to 1/1606. As no remarkable progress occurred in other non-invasive prenatal screening procedures or general health care policies in Belgium, the most reasonable explanation is the use on a large scale of triple test by pregnant women, and the election of termination for most affected pregnancies.

Background Array-CGH is considered as the first-tier investigation used to identify copy number variations. Right now, there is no available data about the genetic etiology of patients with development delay/intellectual disability and congenital malformation in East Africa. Methods Array comparative genomic hybridization was performed in 50 Rwandan patients with development delay/intellectual disability and multiple congenital abnormalities, using the Agilent’s 180 K microarray platform. Results Fourteen patients (28%) had a global development delay whereas 36 (72%) patients presented intellectual disability. All patients presented multiple congenital abnormalities. Clinically significant copy number variations were found in 13 patients (26%). Size of CNVs ranged from 0,9 Mb to 34 Mb. Six patients had CNVs associated with known syndromes, whereas 7 patients presented rare genomic imbalances. Conclusion This study showed that CNVs are present in African population and show the importance to implement genetic testing in East-African countries.