Jean-luc Alessandri - Academia.edu (original) (raw)

Papers by Jean-luc Alessandri

Molecular Genetics and Metabolism Reports

Journal of Pediatric Infectious Diseases

Objective To compare the demographical, clinical and laboratory features, and outcomes of neonate... more Objective To compare the demographical, clinical and laboratory features, and outcomes of neonates with enteroviral meningitis (EVM) with those with bacterial meningitis (BM). Methods A retrospective two-center study was performed in La Réunion Island between January 2008 and December 2018 in hospitalized neonates aged less than 29 days. Patients positive for enterovirus real-time polymerase chain reaction from the cerebrospinal fluid (CSF) were diagnosed with EVM. Neonates with positive CSF culture results for a potentially pathogenic bacterium were diagnosed with BM. Results Compared with their EVM peers (n = 20), BM-infected neonates (n = 14) had lower birth weight, and were more likely to present hypotension and neurological symptoms on admission. Thrombocytopenia, elevated serum procalcitonin, hyperproteinorachia, hypoglycorrhachia, CSF pleocytosis, a bacterial meningitis score >0 were more frequent in the BM-infected group. All BM-infected neonates had at least one abnormal...

Clinical Genetics

Bardet‐Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, re... more Bardet‐Biedl syndrome (BBS) is a rare ciliopathy with variable retinal dystrophy, polydactyly, renal abnormalities, obesity, cognitive impairment, and hypogonadism. Biallelic pathogenic variants have been identified in 24 genes, leading to BBS in an autosomal recessive inheritance pattern. In this study, we investigated a cohort of 16 families (20 individuals) presenting with typical BBS originating from La Réunion Island using sequencing (Sanger and high‐throughput methods) and SNP array. In eight families (12 individuals) we identified the same ARL6/BBS3 variation [c.535G > A, p.(Asp179Asn)]. Bioinformatics and functional analyses revealed an effect of this variant on the splicing of ARL6/BBS3. Owing to the relatively high frequency of this variant, a possible founder effect was suspected. Genotyping of six individuals revealed a common 3.8‐Mb haplotype and estimated the most recent common ancestor to about eight generations confirmed by the known genealogy. Knowledge of this founder effect modifies our diagnostic strategy and enables a personalized genetic counseling for patients from La Réunion Island. Being the first description of BBS patients from La Réunion Island, we could estimate its prevalence between ~1/45000 and ~ 1/66000 individuals.

Human Genetics

SKI pathogenic variations are associated with Shprintzen–Goldberg Syndrome (SGS), a rare systemic... more SKI pathogenic variations are associated with Shprintzen–Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2–47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.

American Journal of Medical Genetics Part C: Seminars in Medical Genetics

The common genes responsible for overgrowth syndromes play key roles in regulating transcription ... more The common genes responsible for overgrowth syndromes play key roles in regulating transcription through histone modification and chromatin modeling. The SETD2 gene encoding a H3K36 trimethyltransferase is implicated in Sotos‐like syndrome. This syndrome is characterized by postnatal overgrowth, macrocephaly, obesity, speech delay, and advanced carpal ossification. We report four new patients with constitutional SETD2 mutations and review nine earlier reported patients. Almost all patients presented with macrocephaly associated with advanced stature and obesity in half of the cases. In addition to these principal manifestations, neurodevelopmental disorders are common such as intellectual disability (83%), autism spectrum disorders (89%), and behavioral difficulties (100%) with aggressive outbursts (83%). A variety of features such as joint hypermobility (29%), hirsutism (33%), and naevi (50%) were also reported. Constitutional SETD2 mutations are intragenic loss‐of‐function variants with truncating (69%) and missense (31%) mutations. Functional studies are necessary to improve understanding of the pathogenicity of some missense SETD2 mutations.

American Journal of Medical Genetics Part A

Go to publication entry in University of Southern Denmark's Research Portal Terms of use This wor... more Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim.

Human Mutation

The authors have realized that a typographic error occurred in Table 1 in the description of sequ... more The authors have realized that a typographic error occurred in Table 1 in the description of sequence variants using HGVS nomenclature, compared to the original manuscript. Indeed, in the columns "nucleotide change" and "amino-acid change", a superscript "a" was inserted for all nonsense mutations and deletions encompassing the last exon instead of an "asterisk" to indicate a translation termination codon. Errors have been corrected throughout the Table 1 and we provide here a revised version of this Table. TA B L E 1 GPC3 mutations associated with Simpson-Golabi-Behmel Syndrome previously reported by other groups Mutation type Position Nucleotide change Amino-acid change Variant reference (dbSNP, ClinVar) Unrelated families in the literature References Missense exon 3 c.886T>A p.(Trp296Arg) rs104894854, RCV000012453.23

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Journal of medical genetics, Jan 4, 2018

The Xq28 duplication involving the gene ( duplication) has been mainly described in male patients... more The Xq28 duplication involving the gene ( duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with p...

European journal of human genetics : EJHG, Mar 12, 2018

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphr... more Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La R...

Clinical Genetics, 2016

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males... more Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not demonstrate a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

PLoS genetics, 2016

Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primar... more Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, prolif...

European Journal of Human Genetics, 2015

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collageno... more Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.European Journal of Human Genetics advance online publication, 2 December 2015; doi:10.1038/ejhg.2015.250.

Journal of Medical Genetics, 2012

Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations fo... more Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.

Human Mutation, 2014

Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenit... more Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle.

European Heart Journal, 2010

Filippatos G, Gheorghiade M. A proposal to standardize dyspnoea measurement in clinical trials of... more Filippatos G, Gheorghiade M. A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach.

Emerging Infectious Diseases, 2011

4. Perkins HA, Busch MP. Transfusionassociated infections: 50 years of relentless challenges and ... more 4. Perkins HA, Busch MP. Transfusionassociated infections: 50 years of relentless challenges and remarkable prog

Clinical Genetics, 2013

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding ... more Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

Cardiology in the Young, 2012

ObjectivesThis study compares the prevalence and perinatal mortality of congenital heart defects ... more ObjectivesThis study compares the prevalence and perinatal mortality of congenital heart defects on La Réunion with European (EUROCAT) standards.Methods and resultsData were extracted from a EUROCAT-affiliated congenital malformations registry, covering 88,025 births during the period 2002–2007, on the whole island territory. A total of 512 congenital heart defects were registered, including 424 live births, 18 foetal deaths from 16 weeks of gestation, and 70 terminations of pregnancy. The total prevalence of congenital heart defects was 5.8 per 1000 births and live birth prevalence was 4.8 per 1000. The total prevalence of non-chromosomal congenital heart defects was 5.1 per 1000 births, of which 3% were perinatal deaths, 33.3% prenatally diagnosed, and 11.6% termination of pregnancy. Severe non-chromosomal congenital heart defects – excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis – occurred in 2.1 per 1000 births, of which 10.3% were perin...

Archives De Pediatrie, 2010

Patients et Méthodes : Étude rétrospective mono-centrique des 29 nouveau-nés hospitalisés en réan... more Patients et Méthodes : Étude rétrospective mono-centrique des 29 nouveau-nés hospitalisés en réanimation pour chylothorax congénital entre 1999 et 2009. Recherche de facteurs de risque de décès en uni-varié par test de Fisher ou de Mann-Whitney. Résultats : 11/29 enfants sont décédés (38 %), 6 d'insuffi sance respiratoire, 3 d'insuffi sance rénale organique et 2 de cause mixte. Sur 4 autopsies, 2 ont retrouvé une hypoplasie pulmonaire, 1 des lymphangiectasies pulmonaires. Les facteurs de risque de décès sont : l'importance de la prématurité (p = 0,039), l'absence de drainage anténatal (64 % de décès versus 22 % ; p = 0,048), la présence d'une anasarque postnatale (75 % de décès versus 24 % ; p = 0,028), la naissance en état de mort apparente (p = 0,01), la nécessité d'une évacuation pleurale postnatale (p = 0,019), l'association à une pathologie générale (83 % de décès versus 26 % ; p = 0,018). Conclusions : La sévérité du chylothorax congénital est principalement liée à son association avec une insuffi sance respiratoire constitutionnelle, persistant malgré un bon contrôle de l'épanchement pleural postnatal. CL048-Dosage de rénine et aldostérone au sang de cordon

R~sum~ L'angiostrongylose. parasitose largement r~pandue darts le Sud-Est asiatique et le Pacifiq... more R~sum~ L'angiostrongylose. parasitose largement r~pandue darts le Sud-Est asiatique et le Pacifique. se manifesto classiquement par une nt6ningile b~nigne h 6osinophiles. Observations.-Cas I. Un garb.on de I I mois. vivant sur I'ile de Mayotte. a present,6 un rash cutan6 transitoire el une ilL%re rapidement a.,;soci~e ~l des convulsions prolong~es, puis .". un coma avec t6tmpar~sie flasque. abolition des r~flexes osl~otendineux et troubles sphinet~riens. II existait une hyper6osinophilie sanguine et une m~ningite h ~osinophiles. Seeondairement. I'enfant a d6velopp6 uric hydroc~phalie triventriculaire conduisant ~l une d6rivation ventficulop~ritoa6ale. Apr~:s 3 semaines d'~volulion. I'enfant est d@~d6 de troubles neurov~g~latifs alors que la s~rologie de I'angiostrongylose s'av~rait positive. Cas 2 et 3. Deux nourrissons vivaat sur V'ile de la R6union oat prO.senti5 ~. I'fige de 10 et 11 mois des vomissements f~briles persistants asseci~s h une irritabilit~ et. pour le cas n ° 3. h une par6sie unilat~rale du neff moleur oculaire exlerne. Toas deux avaient une hyper6osinophilie sanguine et une m~ningite a ~osinophiles. Darts les deux cas. I'~voluiion a ~t~ favorable avec gu~rison compl~:te, et le diagnostic suspect6 d'angiostmngylose a ~t~ confirm~ par la s~rologie. Conclusion.-Nous rapportons le premier cas d'angiostrongylose aux Comores. sot File fmn~;aise de Mayolte. Nous confirmons I'existence de cette parasitose [1 la R6union. Da~s cette r6gioa de I'Oe~an Indien. le nourrisson est la cible privil~gi~e du parasite. A eet fige de la vie. les forints s6v~r-~s voire mortelles. radieulomy61oenct~phalitiques, ne sont pas rares, la contamination '~ partir de I'eseargot terrestre g6ant d'Afrique. Achatimlfidh'a. pouvant ,~tre massive. Angiostrongylus cantoneusis (infestation par) / ~osinophilie / enc~phalomy~lite / radieulite / hydroc~phalle Summary-Eosinophiiic meningitis in Reunion and Mayotte islands caused by Angiostrongylus cantonensis: three cases in infancy including one with fatal radiculomyeloencephalitis and hydrocephalus. Background.-Eoshu~philic menhlgitis caused by Angiostrongylus eantonensis is u'ide.~read bl Southeast Asia and Pat!tic ishouls. Adults develope a transient meningitis with a benign c,,urse but severe or.latal disease may o,.cur ill pediatric patients. Case report.-Case I. A I I-aumth-oM boy/Mug in Mto'otte ishool was hospitalized a few days with fever and skin rash fillhlwiag by seiznre, coma. Jhtccid quadruph,gia, absence of deep tendon reflexes, urinary retenthm olld alto/ ittcamincnce. Eosinophilia was obxen'ed in peripheral bh~od tttld cerehraspinal fluid. He ftlrlher devehJped a trivcotffcolar hydracephahls treated by ventricoloperitoaeal shaat. The chihl died 3 u'eeks late1; A scrodiagnosis qfaogiostroagyhts iofestatioa itxtx restrospe('tivelv established. Case reports 2 and 3.-Two il!hmts. I0 and I I-mamh-oM ;~o3"~. living in Reunion islamL devehqled fi, rer aml