Publications by authors named "Nicolas Chassaing"

79 Publications

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Clin Genet 2021 May 20;99(5):650-661. Epub 2021 Jan 20.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
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http://dx.doi.org/10.1111/cge.13918DOI Listing
May 2021

Parental mosaicism in Marfan and Ehlers-Danlos syndromes and related disorders.

Eur J Hum Genet 2021 May 7;29(5):771-779. Epub 2021 Jan 7.

UF de Génétique Médicale et Cytogénétique, Centre Hospitalier Universitaire de Nîmes, Nîmes, France.

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our "aortic diseases genes" NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient's management.
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http://dx.doi.org/10.1038/s41431-020-00797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110803PMC
May 2021

Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy.

Hum Mutat 2020 12 10;41(12):2167-2178. Epub 2020 Nov 10.

Centre de Génétique Humaine, CHU Franche-Comté, Besançon, France.

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.
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http://dx.doi.org/10.1002/humu.24132DOI Listing
December 2020

Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma.

Eur J Hum Genet 2021 Jan 31;29(1):131-140. Epub 2020 Jul 31.

Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, Toulouse, France.

Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.
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http://dx.doi.org/10.1038/s41431-020-0695-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853074PMC
January 2021

Lessons learned from 40 novel PIGA patients and a review of the literature.

Epilepsia 2020 06 26;61(6):1142-1155. Epub 2020 May 26.

Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.

Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations.

Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches.

Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein.

Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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http://dx.doi.org/10.1111/epi.16545DOI Listing
June 2020

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature.

Mol Genet Genomic Med 2020 05 10;8(5):e1132. Epub 2020 Mar 10.

Service de génétique médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France.

Background: Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants.

Methods: To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype-phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type.

Results: We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients.

Conclusion: Therefore, this report brings additional data for the genotype-phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.
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http://dx.doi.org/10.1002/mgg3.1132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216810PMC
May 2020

Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival.

Genet Med 2020 06 27;22(6):1040-1050. Epub 2020 Feb 27.

Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.

Purpose: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.

Methods: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.

Results: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.

Conclusion: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
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http://dx.doi.org/10.1038/s41436-020-0758-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272323PMC
June 2020

Novel PXDN biallelic variants in patients with microphthalmia and anterior segment dysgenesis.

J Hum Genet 2020 May 3;65(5):487-491. Epub 2020 Feb 3.

UDEAR, UMR 1056 Inserm-Université de Toulouse, Toulouse, France.

Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without microphthalmia.
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http://dx.doi.org/10.1038/s10038-020-0726-xDOI Listing
May 2020

genetic variations and myeloma cast nephropathy.

Clin Kidney J 2019 Oct 15;12(5):639-640. Epub 2019 Jun 15.

Département de Néphrologie et Transplantation d'organes, Centre de référence des maladies rénales rares, Hôpital Rangueil, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

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http://dx.doi.org/10.1093/ckj/sfz071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768300PMC
October 2019

School level of children carrying a HNF1B variant or a deletion.

Eur J Hum Genet 2020 01 3;28(1):56-63. Epub 2019 Sep 3.

Service de Pédiatrie, CHU de Limoges, Limoges, France.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
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http://dx.doi.org/10.1038/s41431-019-0490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906503PMC
January 2020

De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

Am J Hum Genet 2019 09 8;105(3):640-657. Epub 2019 Aug 8.

Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.

The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731360PMC
September 2019

Editorial to the special issue on "Molecular Genetics of Developmental Eye Disorders".

Hum Genet 2019 Sep;138(8-9):793

INSERM1056, Université de Toulouse, Centre de Référence des Anomalies Rares en Génétique Ophtalmologique, Service de Génétique Médicale, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

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http://dx.doi.org/10.1007/s00439-019-02054-0DOI Listing
September 2019

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Am J Hum Genet 2019 02 10;104(2):213-228. Epub 2019 Jan 10.

Service de Génétique Médicale, CHU de Nantes, 44000 Nantes, France; Inserm, CNRS, Univ Nantes, l'institut du thorax, 44000 Nantes, France.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369446PMC
February 2019

Severe gynaecological involvement in Proteus Syndrome.

Eur J Med Genet 2019 Apr 10;62(4):270-272. Epub 2018 Aug 10.

Department of Dermatology, Reference Centre for Rare Skin Diseases, CHU Larrey, Paul Sabatier University, Toulouse, France.

Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe.
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http://dx.doi.org/10.1016/j.ejmg.2018.08.003DOI Listing
April 2019

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes.

Hum Genet 2019 Sep 4;138(8-9):1051-1069. Epub 2018 Jul 4.

UDEAR, UMR 1056 Inserm, Université de Toulouse, Toulouse, France.

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.
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http://dx.doi.org/10.1007/s00439-018-1896-xDOI Listing
September 2019

New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies.

Hum Genet 2019 Sep 20;138(8-9):1027-1042. Epub 2018 Feb 20.

Genetics Service, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype-phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.
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http://dx.doi.org/10.1007/s00439-018-1875-2DOI Listing
September 2019

Identification of PITX3 mutations in individuals with various ocular developmental defects.

Ophthalmic Genet 2018 06 6;39(3):314-320. Epub 2018 Feb 6.

a UDEAR , Université de Toulouse, UMRS 1056 INSERM-Université Paul Sabatier , Toulouse , France.

Background: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders.

Materials And Methods: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea.

Results: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract.

Conclusions: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.
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http://dx.doi.org/10.1080/13816810.2018.1430243DOI Listing
June 2018

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

Genome Med 2018 01 9;10(1). Epub 2018 Jan 9.

The Jackson Laboratory for Genomic Medicine, 06032, Farmington, USA.

Background: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification.

Methods: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals.

Results: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD.

Conclusions: Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.
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http://dx.doi.org/10.1186/s13073-017-0510-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759841PMC
January 2018

Hepatocyte Nuclear Factor-1 Controls Mitochondrial Respiration in Renal Tubular Cells.

J Am Soc Nephrol 2017 Nov 24;28(11):3205-3217. Epub 2017 Jul 24.

Institut National de la Santé et de la Recherche Médicale, U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France;

AKI is a frequent condition that involves renal microcirculation impairment, infiltration of inflammatory cells with local production of proinflammatory cytokines, and subsequent epithelial disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor coactivator 1- (PPARGC1A), a coactivator of the transcription factor PPAR- that controls mitochondrial biogenesis and function, has a pivotal role in the early dysfunction of the proximal tubule and the subsequent renal repair. Here, we evaluated the potential role of hepatocyte nuclear factor-1 (HNF-1) in regulating PPARGC1A expression in AKI. In mice, endotoxin injection to induce AKI also induced early and transient inflammation and PPARGC1A inhibition, which overlapped with downregulation of the HNF-1 transcriptional network. , exposure of proximal tubule cells to the inflammatory cytokines IFN- and TNF- led to inhibition of HNF-1 transcriptional activity. Moreover, inhibition of HNF-1 significantly reduced PPARGC1A expression and altered mitochondrial morphology and respiration in proximal tubule cells. Chromatin immunoprecipitation assays and PCR analysis confirmed HNF-1 binding to the promoter in mouse kidneys. We also demonstrated downregulation of renal expression in a patient with an germinal mutation. Thus, we propose that HNF-1 links extracellular inflammatory signals to mitochondrial dysfunction during AKI partly PPARGC1A signaling. Our findings further strengthen the view of -related nephropathy as a mitochondrial disorder in adulthood.
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http://dx.doi.org/10.1681/ASN.2016050508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661272PMC
November 2017

Both a frameshift and a missense mutation of the STRA6 gene observed in an infant with the Matthew-Wood syndrome.

Birth Defects Res 2017 Mar;109(4):251-253

Obstetrics, Gynecology, and Gynecological Oncology, Medical University of Lodz, Lodz, Poland.

Background: The Matthew-Wood syndrome is associated with mutations of the STRA6 gene. It combines a pulmonary agenesis/hypoplasia; microphthalmia/anophthalmia; congenital cardiac, digestive, and urogenital malformations; and diaphragmatic defects.

Case: A 23-year-old nulliparous woman was referred to our center after a fetal ultrasound examination at 26 weeks of pregnancy revealed an abnormal head shape, a heart malformation, multiple cysts in both kidneys, and dilated ureters. A male baby (46, XY; 3600g; Apgar score 1) was delivered at 38 weeks of gestation and died 1 hr later due to respiratory failure. The diagnosis of Matthew-Wood syndrome was suspected given the association of bilateral anophthalmia, agenesis of the left lung, and heart and kidney defects. It was confirmed by the identification of two deleterious mutations of the STRA6 gene.

Results: The child was a compound heterozygote for two previously reported mutations, a paternally inherited missense mutation (c.878C>T [p.Pro293Leu] and a maternally inherited frameshift mutation (c.50_52delACTinsCC [p. Asp17Alafs*55]), producing a premature stop codon.

Conclusion: The diagnosis of Matthew-Wood syndrome should be considered in all fetuses with microphthalmia/anophthalmia. It requires an extensive ultrasound/MRI examination of the lung, heart, and diaphragm. Birth Defects Research 109:251-253, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdra.23465DOI Listing
March 2017

Mosaic Focal Dermal Hypoplasia (Goltz Syndrome) in Two Female Patients.

Acta Derm Venereol 2017 Jul;97(7):853-854

Department of Dermatology, Toulouse University Hospital, Toulouse, 24 chemin de Pouvourville TSA 30030, 31059 Toulouse cedex 9, France.

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http://dx.doi.org/10.2340/00015555-2648DOI Listing
July 2017

Genetic Advances in Microphthalmia.

J Pediatr Genet 2016 Dec 16;5(4):184-188. Epub 2016 Sep 16.

Department of Medical Genetics, Purpan University Hospital, Toulouse, France; U1056 INSERM-FRE 3742 CNRS-Université Toulouse III, Toulouse, France.

Congenital ocular anomalies such as anophthalmia and microphthalmia (AM) are severe craniofacial malformations in human. The etiologies of these ocular globe anomalies are diverse but the genetic origin appears to be a predominant cause. Until recently, genetic diagnosis capability was rather limited in AM patients and only a few genes were available for routine genetic testing. While some issues remain poorly understood, knowledge regarding the molecular basis of AM dramatically improved over the last years with the development of new molecular screening technologies. Thus, the genetic cause is now identifiable in more than 50% of patients with a severe bilateral eye phenotype and in around 30% of all AM patients taken together. Such advances in the knowledge of these genetic bases are important as they improve the quality of care, in terms of diagnosis, prognosis, and genetic counseling delivered to the patients and their families.
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http://dx.doi.org/10.1055/s-0036-1592350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123893PMC
December 2016

Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature.

Eur J Hum Genet 2016 01 2;25(1):43-51. Epub 2016 Nov 2.

FHU TRANSLAD, Centre de Référence Maladies Rares de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.

Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.
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http://dx.doi.org/10.1038/ejhg.2016.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159768PMC
January 2016

Extensive Post-zygotic Mosaicism of KRT1 or KRT10 Mutation Mimicking Classical Epider-molytic Ichthyosis.

Acta Derm Venereol 2017 03;97(3):387-388

Department of Dermatology, Toulouse University Hospital, Toulouse, 24 chemin de Pouvourville TSA 30030, FR-31059 Toulouse cedex 9, France.

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http://dx.doi.org/10.2340/00015555-2542DOI Listing
March 2017

Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens.

Am J Hum Genet 2016 08 28;99(2):437-42. Epub 2016 Jul 28.

Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. Electronic address:

In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974083PMC
August 2016

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway.

Hum Mutat 2016 12 23;37(12):1329-1339. Epub 2016 Aug 23.

Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.

Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.
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http://dx.doi.org/10.1002/humu.23038DOI Listing
December 2016

Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum.

J Hum Genet 2016 Aug 19;61(8):693-9. Epub 2016 May 19.

CHU Bordeaux, Hôpital Pellegrin, Department of Medical Genetics, Centre de Référence des Anomalies du Développement Embryonnaire, Bordeaux cedex, France.

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.
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http://dx.doi.org/10.1038/jhg.2016.37DOI Listing
August 2016

Complete Penetrance and Absence of Intrafamilial Variability in a Large Family with Hereditary Leiomyomatosis and Renal Cell Carcinoma.

Dermatology 2016 5;232(3):293-7. Epub 2016 May 5.

Service de Dermatologie, CHU Larrey, Universitx00E9; Paul Sabatier, Toulouse, France.

Background: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial disorder due to FH mutation. Despite a considerable increase in information about the genetic background, inter- and intrafamilial phenotypic variability/penetrance are not well documented.

Objective: To describe a large French HLRCC family and provide new data on penetrance and intrafamilial variability.

Materials And Methods: The whole family was contacted for clinical examination, skin biopsy, uterine and kidney imagery and molecular analysis.

Results: The family included 22 members in 3 generations. The second generation consisted of 13 members who were older than the expected age of onset of disease manifestations. Of the 12 available members of this second generation, 6 (1 man and 5 women, aged 44-57 years) had a novel FH mutation. All had the same mild phenotype with cutaneous asymptomatic leiomyomas, uterine fibroids (if women) and no kidney tumor. The other 6 members not bearing the familial mutation had normal clinical and radiological findings. In this second generation, the penetrance was therefore complete, and there was no intrafamilial variability in the clinical expression of the mutation.

Conclusion: This study provides additional data on genotype/phenotype correlation, intrafamilial variability and penetrance that should help to improve prognosis and genetic counseling.
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http://dx.doi.org/10.1159/000445430DOI Listing
April 2017

Gain-of-Function Mutations in RARB Cause Intellectual Disability with Progressive Motor Impairment.

Hum Mutat 2016 08 9;37(8):786-93. Epub 2016 May 9.

CHU Sainte-Justine Research Center, Montréal, H3T 1C5, Canada.

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.
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http://dx.doi.org/10.1002/humu.23004DOI Listing
August 2016