Jelena Martinovic | Paris Sud XI University (original) (raw)

Papers by Jelena Martinovic

Clinical Genetics, 2019

Bardet‐Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesit... more Bardet‐Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Pathology, 2008

Birth defects of the brain result from malformation and disruptions. They remain an important cau... more Birth defects of the brain result from malformation and disruptions. They remain an important cause of childhood morbidity and mortality. Effective treatments are scarce and prevention strategies limited. As aetiological screening is costly and uncertain, genetic counselling remains empirical in most cases. A pathological study of the malformed brain is the best approach to establish the diagnosis of a brain malformation. It relies on a thorough description of the brain, including its size, external pattern and/or internal configuration. When evaluating a malformed brain two major factors should be considered: (1) malformations result from an arrest of the development at a given time, interfering with subsequent stages of development, leading to a sequence of malformations where the 'primary event' should be distinguished from 'secondary changes'; (2) there is no obvious causal relationship when the final morphology of the central nervous system is considered. For example, mutations in different genes involved in a signalling pathway may result in a similar pattern of malformations. In addition, signalling pathways may be a possible target of toxic agents, mimicking malformations caused by genetic factors. A precise diagnosis will allow rational aetiological screening, with direct benefit for the family, which may serve other families. In addition, it helps to establish a quality assurance process for medical practice, collect solid epidemiological data and conduct research studies. Because of discrepancies observed between human diseases and animal models, research on human material is mandatory. This requires collection of organs, tissues and cells within a legal and ethical framework.

Journal of Medical Genetics, 2011

Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and... more Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples. Objective and Methods To better characterize the involvement of RET and GDNF in kidney development defects, we studied a series of 105 fetuses with bilateral defects including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs and RET intron 1 were analysed. Copy number variations (CNVs) at these loci were also investigated. Results We identified: (i) a low frequency (< 7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (ii) no GDNF mutation; (iii) similar allele frequencies in patients and controls for most SNP variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs. 2%, P=0.01); (iv) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (v) absence of CNVs. Conclusion These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.

Clinical Journal of the American Society of Nephrology, 2013

Background and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a freq... more Background and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy. Design, setting, participants, & measurements This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy. Results This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. Conclusions Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.

European Journal of Medical Genetics

Practical Manual of Fetal Pathology, 2021

In no other area of anatomical pathology, does law, ethics, and religion play such a large role t... more In no other area of anatomical pathology, does law, ethics, and religion play such a large role than with the mortuary and the autopsy, and pathologists dealing with autopsies, especially those of children, babies, and fetuses, are particularly sensitive, and pathologists need to be aware of the wider legal and social issues involved. Over the last 20 years or so, many national inquiries and investigations have focused on this area, becoming front page news and often leading to similar investigations in other countries. These issues have led to huge distress to the families and professional staff in pathology departments, and sometimes to introduction of new laws, regulations, and codes of practice. This review is not meant to give current information for every country. The laws and the guidelines from national and international bodies change and society is also changing. The review addresses many areas related to the postmortem procedures in mortuary and fetal/perinatal pathology d...

American Journal of Obstetrics and Gynecology

BACKGROUND Despite undisputable benefits, midtrimester prenatal surgery (20-24 weeks) is not a cu... more BACKGROUND Despite undisputable benefits, midtrimester prenatal surgery (20-24 weeks) is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery.Indeed, the timing and intensity of intrauterine spinal cord injury remains ill-defined. Based on postmortem pathology, we describe the natural history of neuronal loss in utero. METHODS Pathology findings were analyzed in 186 cases of isolated MMC with a lesion level between S1 and T1. Using a case-control cross-sectional design we investigated the timewise progression and topographical extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 cases meeting quality criteria for cell counting. These were expressed as observed/expected (O/E) ratios, after matching for gestational age and spinal level with 41 controls. RESULTS Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe and progressive neuronal loss: the O/E count dropped from 17% to ≤ 2% after 16 weeks. The neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the O/E motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, although in much smaller proportions. The O/E proportion of motor neurons was not correlated with the level of the MMC. CONCLUSIONS Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could avoid Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord and avoid the extension to the upper spinal cord.

Morphologie

Introduction/objectifs La connaissance de l’anatomie du plancher pelvien musculaire masculin est ... more Introduction/objectifs La connaissance de l’anatomie du plancher pelvien musculaire masculin est importante pour la realisation de la prostatectomie et de la protectomie. Decrire l’anatomie et l’innervation du plancher pelvien musculaire masculin. Materiels/patients et methodes Nous avons realise une etude histologique et immunohistochimique chez trois fœtus humains masculins avec des coupes seriees de bassin. Les coupes etaient traitees par le trichrome de Masson puis immuno-marquees pour detecter les nerfs, les fibres somatiques, les fibres autonomes sympathiques et parasympathiques, les fibres nitriergiques, le muscle lisse et le muscle strie. Les coupes bidimensionnelles obtenues ont ete scannees par un scanner de haute resolution optique. Resultats Au sein du plancher musculaire pelvien, nous avons individualise un compartiment central median (CCM) forme par des cellules musculaires lisses. Le CCM est limite par le rectum en arriere, l’uretre en avant et le muscle elevateur de l’anus lateralement. On distingue en son sein : – un contingent posterieur en arriere du rectum ; – un contingent anterieur en avant du rectum. Ces deux contingents sont en continuite. Ce compartiment s’insere sur le muscle elevateur de l’anus, le rectum, le sphincter lisse de l’uretre et le muscle bulbo-spongieux. Il est innerve par le systeme nerveux autonome via le plexus hypogastrique inferieur. Conclusion Le plancher musculaire pelvien masculin contient une zone mediale faite de cellules musculaires lisses sous influence nerveuse autonome. Cette donnee est d’une importance majeure pour les chirurgiens dans le but d’eviter les lesions nerveuses, du rectum et de l’uretre au cours de la prostatectomie radicale et de la protectomie.

Prenatal Diagnosis

To evaluate neonatal mortality and morbidity up to 6 months in neonates with congenital diaphragm... more To evaluate neonatal mortality and morbidity up to 6 months in neonates with congenital diaphragmatic hernia (CDH) with or without a hernia sac.

Human Molecular Genetics

Mutations in KIF14 have previously been associated with either severe, isolated or syndromic micr... more Mutations in KIF14 have previously been associated with either severe, isolated or syndromic microcephaly with renal hypodysplasia (RHD). Syndromic microcephaly-RHD was strongly reminiscent of clinical ciliopathies, relating to defects of the primary cilium, a signalling organelle present on the surface of many quiescent cells. KIF14 encodes a mitotic kinesin which plays a key role at the midbody during cytokinesis and has not previously been shown to be involved in cilia-related functions. Here, we analysed four families with foetuses presenting with the syndromic form and harbouring biallelic variants in KIF14. Our functional analyses show that the identified variants severely impact the activity of KIF14 and likely correspond to loss-of-function mutations. Analysis in human foetal tissues further revealed the accumulation of KIF14-positive midbody remnants in the lumen of ureteric bud tips indicating a shared function of KIF14 during brain and kidney development. Subsequently, analysis of a kif14 mutant zebrafish line showed a conserved role for this mitotic kinesin. Interestingly, ciliopathy-associated phenotypes were also present in mutant embryos, supporting a potential direct or indirect role for KIF14 at cilia. However, our in vitro and in vivo analyses did not provide evidence of a direct role for KIF14 in ciliogenesis and suggested that loss of kif14 causes ciliopathy-like phenotypes through an accumulation of mitotic cells in ciliated tissues. Altogether, our results demonstrate that KIF14 mutations result in a severe syndrome associating microcephaly and RHD through its conserved function in cytokinesis during kidney and brain development.

Taiwanese journal of obstetrics & gynecology, 2017

Isochromosome of the long arm of chromosome 20 (i(20q)) is a rare structural abnormality in prena... more Isochromosome of the long arm of chromosome 20 (i(20q)) is a rare structural abnormality in prenatal diagnosis. Thirty prenatal cases of mosaic i(20q) have been reported, among which only four are associated with fetal malformations. We describe a new prenatal case of i(20q) with fetal malformations. We also observed a discrepancy between uncultured and cultured amniotic fluid cells by using conventional cytogenetic, fluorescence in situ hybridization and array-SNP analysis. The short arm deletion of chromosome 20 arising from the isochromosome encompassed two candidate genes PAX1 and JAG1 involved in cranio-facial and vertebral development. The data would allow establishing a phenotype-genotype correlation. Thus, we proposed to define a recognizable syndrome combining cranio-facial dysmorphism, vertebral bodies' anomalies, feet and cerebral malformations.

Birth defects research, Jan 22, 2018

The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mu... more The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism. A targeted exome sequencing of morbid genes causing cerebral malformations identified novel RTTN compound heterozygous mutations in a family where three pregnancies were terminated because a severe fetal microcephaly was diagnosed. An autopsy performed on the second sib showed moderate growth restriction and a microcephaly with simplified gyral pattern. The histopathological study discovered a malformed cortical plate. The present study confirms the involvement of RTTN gene mutations in microcephaly with simplified gyral pattern and describes the observed abnormal neuropathological findings.

European journal of medical genetics, 2018

Proximal 19p13.12 microdeletion has been rarely reported. Only five postnatal cases with intellec... more Proximal 19p13.12 microdeletion has been rarely reported. Only five postnatal cases with intellectual disability, facial dysmorphism, branchial arch defects and overlapping deletions involving proximal 19p13.12 have been documented. Two critical intervals were previously defined: a 700 kb for branchial arch defects and a 350 kb for hypertrichosis-synophrys-protruding front teeth. We describe the first prenatal case, a fetal death in utero at 39 weeks of gestation. Agilent 180K array-CGH analysis identified a heterozygous interstitial 745 kb deletion at 19p13.12 chromosome region, encompassing both previously reported critical intervals, including at least 6 functionally relevant genes: NOTCH3, SYDE1, AKAP8, AKAP8L, WIZ and BRD4. Quantitative PCR showed that the deletion occurred de novo with a median size of 753 kb. NOTCH3 and SYDE1 were candidate genes for placental pathology whilst AKAP8, AKAP8L, WIZ and BRD4 were highly expressed in the branchial arches. Molecular characterizatio...

Brain : a journal of neurology, 2018

See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.Vein of Galen ... more See Meschia (doi:10.1093/brain/awy066) for a scientific commentary on this article.Vein of Galen aneurysmal malformation is a congenital anomaly of the cerebral vasculature representing 30% of all paediatric vascular malformations. We conducted whole exome sequencing in 19 unrelated patients presenting this malformation and subsequently screened candidate genes in a cohort of 32 additional patients using either targeted exome or Sanger sequencing. In a cohort of 51 patients, we found five affected individuals with heterozygous mutations in EPHB4 including de novo frameshift (p.His191Alafs*32) or inherited deleterious splice or missense mutations predicted to be pathogenic by in silico tools. Knockdown of ephb4 in zebrafish embryos leads to specific anomalies of dorsal cranial vessels including the dorsal longitudinal vein, which is the orthologue of the median prosencephalic vein and the embryonic precursor of the vein of Galen. This model allowed us to investigate EPHB4 loss-of-fun...

Clinica chimica acta; international journal of clinical chemistry, Jan 22, 2018

Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as non... more Hydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality. The hydrops fetalis (HydFet) panel was designed to cover the coding regions and flanking intronic sequences of 41 genes. A retrospective study of amniotic fluid samples from 40 subjects was conducted. A prospective study was subsequently initiated, and six samples were analyzed using the NGS panel. Five IEM diagnoses wer...

American journal of human genetics, Jan 2, 2017

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic ... more Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Fem...

American journal of obstetrics and gynecology, Jan 5, 2017

Injury to the levator ani muscle or pelvic nerves during pregnancy and vaginal delivery are respo... more Injury to the levator ani muscle or pelvic nerves during pregnancy and vaginal delivery are responsible for pelvic floor dysfunction. To demonstrate the presence of smooth muscular cell areas within the levator ani muscle and describe their localization and innervation. Five female human fetuses were studied after approval from the French Biomedicine Agency. Specimens were serially sectioned and stained by Masson's trichrome and immunostained for striated and smooth muscle, as well as for somatic, adrenergic, cholinergic, and nitriergic nerve fibers. Slides were digitized for 3D reconstruction. One fetus was reserved for electronic microscopy. We explored the structure and innervation of the levator ani muscle. Smooth muscular cell beams were connected externally to the anococcygeal raphe and the levator ani muscle and with the longitudinal anal muscle sphincter. The caudalmost part of the pubovaginal muscle was found to bulge between the rectum and the vagina. This bulging was ...

Birth Defects Research

Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often pred... more Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often predicts a poor prognosis. The etiology involves both genetic and nongenetic factors with diverse pathogenic mechanisms. We describe the neuropathological features of CVD in a large cohort of fetuses. The goals are to determine the physiopathological mechanisms and etiologies. We retrospectively analyzed a series of 130 fetuses examined at the Necker University Hospital following termination of pregnancy between January 2000 and December 2014. Chiari II and Dandy-Walker malformations were excluded from our study population. Karyotype and/or array comparative genomic hybridization were performed in all cases. Targeted Sanger sequencing or next generation sequencing were carried out in 34 and 5 cases, respectively. We distinguished four groups of pathological entities: (1) midbrain/hindbrain patterning defects (54 cases, 42%), mainly related to aqueduct of Sylvius anomalies (atresia or stenosis); (2) cerebral cytoarchitectonic disorders (16 cases, 12%), essentially resulting from arachnoidal neuroglial ectopia; (3) hemorrhagic and perfusion failure (42 cases, 32%); and (4) nonspecific CVD (18 cases, 14%), without apparent obstruction, cortical malformation, or clastic injury. Although the pathogenic mechanisms of CVD were identified in 86% of cases, the causes, both acquired and genetic, were recognized in 21% of cases only. The neuropathological analysis is a powerful tool in the diagnosis of the fetal CVD pathogenic mechanisms and to identify homogeneous groups. The paucity of molecular diagnosis, notably in the major groups of midbrain/hindbrain patterning defects and hemorrhagic and perfusion failure, highlights the needs of future research to improve our current knowledge on CVD causes. Birth Defects Research, 2017. © 2017 Wiley Periodicals, Inc.