Publications by authors named "Yoann Vial"

14 Publications

  • Page 1 of 1

The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.

Eur J Hum Genet 2021 03 20;29(3):524-527. Epub 2020 Oct 20.

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.
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http://dx.doi.org/10.1038/s41431-020-00743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940614PMC
March 2021

Cherubism as a systemic skeletal disease: evidence from an aggressive case.

BMC Musculoskelet Disord 2020 Aug 21;21(1):564. Epub 2020 Aug 21.

Laboratoire de Physiopathologie Orale Moléculaire, INSERM UMRS 1138, Equipe 5, Centre de Recherche de Cordeliers, 75006, Paris, France.

Background: Cherubism is a rare autosomal dominant genetic condition caused by mutations in the SH3BP2 gene. This disease is characterized by osteolysis of the jaws, with the bone replaced by soft tissue rich in fibroblasts and multinuclear giant cells. SH3BP2 is a ubiquitous adaptor protein yet the consequences of SH3BP2 mutation have so far been described as impacting only face. Cherubism mouse models have been generated and unlike human patients, the knock-in mice exhibit systemic bone loss together with a systemic inflammation.

Case Presentation: In light of these observations, we decided to search for a systemic cherubism phenotype in a 6-year-old girl with an aggressive cherubism. We report here the first case of cherubism with systemic manifestations. Bone densitometry showed low overall bone density (total body Z-score = - 4.6 SD). Several markers of bone remodelling (CTx, BALP, P1NP) as well as inflammation (TNFα and IL-1) were elevated. A causative second-site mutation in other genes known to influence bone density was ruled out by sequencing a panel of such genes.

Conclusions: If this systemic skeletal cherubism phenotype should be confirmed, it would simplify the treatment of severe cherubism patients and allay reservations about applying a systemic treatment such as those recently published (tacrolimus or imatinib) to a disease heretofore believed to be localised to the jaws.
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http://dx.doi.org/10.1186/s12891-020-03580-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441549PMC
August 2020

T-Cell Acute Lymphoblastic Leukemia in a Young Adult With Thrombocytopenia-absent Radius Syndrome: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2021 08;43(6):232-235

Hematology Adolescent and Young Adults Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris.

Thrombocytopenia-absent radius (TAR) syndrome is a rare inherited bone marrow failure syndrome not generally associated with acute leukemia. The authors report a case of T-cell acute lymphoblastic leukemia in an adult female individual newly diagnosed with TAR syndrome. A 347-kb microdeletion of chromosome 1q21.1 involving the RBM8A gene was detected within a gain of whole chromosome 1. Next-generation sequencing on fibroblasts confirmed germline heterozygous deletion of RBM8A but on the other allele, noncoding low-frequency regulatory single-nucleotide polymorphism of RBM8A (rs139428292; rs201779890) were not found. The tolerance of the treatment was unusual and mostly marked by a slow hematopoietic recovery leading to a 6-month delay at the beginning of the maintenance phase. Only 5 cases of acute leukemia were reported in patients with TAR syndrome in the literature: 4 acute myeloid leukemia and one B-cell acute lymphoblastic leukemia. This is the first report of T-cell acute lymphoid leukemia occurring in the context of TAR syndrome.
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http://dx.doi.org/10.1097/MPH.0000000000001919DOI Listing
August 2021

Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications.

Eur J Hum Genet 2021 01 12;29(1):51-60. Epub 2020 Aug 12.

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.
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http://dx.doi.org/10.1038/s41431-020-00708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852574PMC
January 2021

Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study.

Diabetes Care 2020 06 9;43(6):1191-1199. Epub 2020 Apr 9.

Department of Pediatric Endocrinology, Gynecology, and Diabetology, Necker-Enfants Malades Teaching Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute Affiliate, Paris, France.

Objective: Transient neonatal diabetes mellitus (TNDM) occurs during the 1st year of life and remits during childhood. We investigated glucose metabolism and socioeducational outcomes in adults.

Research Design And Methods: We included 27 participants with a history of TNDM currently with ( = 24) or without ( = 3) relapse of diabetes and 16 non-TNDM relatives known to be carriers of causal genetic defects and currently with ( = 9) or without ( = 7) diabetes. Insulin sensitivity and secretion were assessed by hyperinsulinemic-euglycemic clamp and arginine-stimulation testing in a subset of 8 TNDM participants and 7 relatives carrying genetic abnormalities, with and without diabetes, compared with 17 unrelated control subjects without diabetes.

Results: In TNDM participants, age at relapse correlated positively with age at puberty ( = 0.019). The mean insulin secretion rate and acute insulin response to arginine were significantly lower in TNDM participants and relatives of participants with diabetes than in control subjects (median 4.7 [interquartile range 3.7-5.7] vs. 13.4 [11.8-16.1] pmol/kg/min, < 0.0001; and 84.4 [33.0-178.8] vs. 399.6 [222.9-514.9] µIU/mL, = 0.0011), but were not different between participants without diabetes (12.7 [10.4-14.3] pmol/kg/min and 396.3 [303.3-559.3] µIU/mL, respectively) and control subjects. Socioeducational attainment was lower in TNDM participants than in the general population, regardless of diabetes duration.

Conclusions: Relapse of diabetes occurred earlier in TNDM participants compared with relatives and was associated with puberty. Both groups had decreased educational attainment, and those with diabetes had lower insulin secretion capacity; however, there was no difference in insulin resistance in adulthood. These forms of diabetes should be included in maturity-onset diabetes of the young testing panels, and relatives of TNDM patients should be screened for underlying defects, as they may be treated with drugs other than insulin.
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http://dx.doi.org/10.2337/dc19-0324DOI Listing
June 2020

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

Pediatr Dermatol 2020 May 10;37(3):541-544. Epub 2020 Mar 10.

Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), APHP, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.
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http://dx.doi.org/10.1111/pde.14139DOI Listing
May 2020

Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

Hum Mutat 2020 02 27;41(2):512-524. Epub 2019 Nov 27.

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.
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http://dx.doi.org/10.1002/humu.23948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496698PMC
February 2020

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report.

Eur J Med Genet 2019 Aug 14;62(8):103704. Epub 2019 Jun 14.

Center for Human Genetics, Centre Hospitalier Universitaire, University of Liege, Liege, Belgium.

Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.
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http://dx.doi.org/10.1016/j.ejmg.2019.103704DOI Listing
August 2019

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.

Am J Hum Genet 2019 06 23;104(6):1223-1232. Epub 2019 May 23.

Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré, 75019 Paris, France; INSERM UMR 1141 - Université de Paris, 75019 Paris, France.

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562003PMC
June 2019

Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes.

Eur J Med Genet 2019 Dec 22;62(12):103588. Epub 2018 Nov 22.

Department of Genetics, APHP-Robert DEBRE University Hospital, Sorbonne Paris-Cité University, and INSERM UMR 1141, Paris, France. Electronic address:

The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities.
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http://dx.doi.org/10.1016/j.ejmg.2018.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594898PMC
December 2019

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

Hum Mutat 2018 03 16;39(3):319-332. Epub 2018 Jan 16.

Service de pédiatrie, Hôpital Nord Ouest-Villefranche, Gleize, France.

Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
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http://dx.doi.org/10.1002/humu.23381DOI Listing
March 2018

Phosphoglycerate dehydrogenase (PHGDH) deficiency without epilepsy mimicking primary microcephaly.

Am J Med Genet A 2017 Jul 25;173(7):1936-1942. Epub 2017 Apr 25.

Department of Genetics, APHP-Robert DEBRE University Hospital, Paris VII-Denis Diderot Medical School and INSERM UMR1141, Paris, France.

Phosphoglycerate dehydrogenase (PHGDH) deficiency (OMIM 256520) is a rare autosomal recessive disorder of serine synthesis, with mostly severe congenital microcephaly, caused by mutations in the PHGDH gene. Fourteen patients reported to date show severe, early onset, drug resistant epilepsy. In a cohort of patients referred for primary microcephaly, compound heterozygosity for two unreported variants in PHGDG was identified by exome sequencing in a pair of sibs who died aged 4.5 months and 4.5 years. They had severe neurological involvement with congenital microcephaly, disorganized EEG, and progressive spasticity, but never had seizures. Exome usage in clinical practice is likely to lead to an expansion of the clinical spectrum of known disorders.
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http://dx.doi.org/10.1002/ajmg.a.38217DOI Listing
July 2017

In vitro influence of fatty acids and bilirubin on binding of mycophenolic acid to human serum albumin.

J Pharm Biomed Anal 2011 Feb 29;54(3):607-9. Epub 2010 Sep 29.

Laboratoire de pharmacologie-toxicologie, service de Pharmacie, GH Cochin Saint Vincent de Paul, 75014 Paris, APHP, France.

Mycophenolic acid (MPA) is 98-99% bound to albumin. Because MPA is restrictively cleared and has a low extraction coefficient, increase in its free fraction related to decreased albumin binding results in lower total concentrations but unchanged unbound concentrations. Multiple factors, including hypoalbuminemia, impaired renal function, and accumulated mycophenolic acid glucuronide are known to reduce MPA protein binding. Little is known about the influence of fatty acids and bilirubin on this issue. By using quenching fluorescence method, the aims of this study were to investigate in vitro the binding properties of MPA, then the influence of myristic acid and bilirubin on MPA binding to albumin. The estimate of dissociation constant (Kd) of MPA was 13.2 [CI 95 12.7-13.8] μM. In the presence of myristic acid (concentration range 4-100 μM), apparent Kd (Kd(app)) of MPA was approximately 1.5-10-fold greater. For myristic acid/albumin molar ratio reachable in clinical settings (2:1 and 5:1), Kd(app) of MPA rose about a factor 1.5 and 2.2, respectively. In the presence of bilirubin (concentration range 0.5-5 μM), Kd(app) of MPA was approximately 1.5-5-fold greater than MPA Kd. For bilirubin/albumin molar ratio reachable in clinical settings (1:4 and 1:2), Kd(app) of MPA rose about a factor 1.5 and 1.9, respectively. These data suggest that hypertriglyceridemia or cholestasis may significantly increase MPA free fraction in clinical settings, thereby lowering MPA total concentration in plasma while the free concentration remains unchanged. These results may help to optimize the therapeutic drug monitoring of MPA.
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http://dx.doi.org/10.1016/j.jpba.2010.09.032DOI Listing
February 2011
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