0000000000331688
AUTHOR
Arthur Sorlin
Fertilité chez la femme McCune Albright : une étude de cas axée sur l’AMH en tant que marqueur du dysfonctionnement ovarien et revue systématique
La plupart des filles porteuses d’un syndrome de McCune Albright (SMA) presentent une puberte precoce, causee par le developpement de kystes ovariens responsables d’une hyperestrogenie. Apres la puberte, peuvent etre retrouves troubles du cycle et infertilite. Nous avons souhaite faire le point sur la fertilite et la grossesse chez les femmes presentant un SMA, par un report de cas detaille et une revue exhaustive de la litterature. Nous presentons le cas d’une femme infertile, unilateralement ovariectomise, prise en charge par FIV. La stimulation a necessite des doses elevees de FSH. Huit ovocytes avec de nombreuses anomalies morphologiques ont ete recuperes, avec developpement de 4 embryo…
High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics
ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) st…
Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light
The expanding use of exome sequencing (ES) in diagnosis generates a huge amount of data, including untargeted mitochondrial DNA (mtDNA) sequences. We developed a strategy to deeply study ES data, focusing on the mtDNA genome on a large unspecific cohort to increase diagnostic yield. A targeted bioinformatics pipeline assembled mitochondrial genome from ES data to detect pathogenic mtDNA variants in parallel with the "in-house" nuclear exome pipeline. mtDNA data coming from off-target sequences (indirect sequencing) were extracted from the BAM files in 928 individuals with developmental and/or neurological anomalies. The mtDNA variants were filtered out based on database information, cohort …
Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials
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 pat…
De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features
IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or with…
Cerebriform sebaceous nevus: a subtype of organoid nevus due to specific postzygotic FGFR2 mutations.
Background Postzygotic mutations in FGFR2 have been identified in mosaic forms of acne, keratinocytic epidermal nevi, nevoid acanthosis nigricans / rounded and velvety epidermal nevus and in two fetuses with papillomatous pedunculated sebaceous nevus (PPSN). Objectives To determine the clinical and genetic characteristics of children with cerebriform, papillomatous, and pedunculated variants of sebaceous nevi. Methods Infants diagnosed with sebaceous nevi characterized by a cerebriform, papillomatous, and/or pedunculated morphology over a 10-year period (2010 - 2019) at three pediatric dermatology centers in Switzerland and France were included in this case series. Clinical and histological…
Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants
Next-generation sequencing has revealed the major impact of de novo variants (DNVs) in developmental disorders (DD) such as intellectual disability, autism, and epilepsy. However, a substantial fraction of these predicted pathogenic DNVs remains challenging to distinguish from background DNVs, notably the missense variants acting via nonhaploinsufficient mechanisms on specific amino acid residues. We hypothesized that the detection of the same missense variation in at least two unrelated individuals presenting with a similar phenotype could be a powerful approach to reveal novel pathogenic variants. We looked for variations independently present in both our database of >1200 solo exomes and…
Fertility in McCune Albright syndrome female: A case study focusing on AMH as a marker of ovarian dysfunction and a literature review.
Abstract Background The molecular basis of McCune Albright syndrome (MAS) is a recurrent GNAS Postzygotic gain of function sporadic mutation, resulting in a mosaic disease. Most of girls present precocious puberty, caused by the development of recurrent ovarian cysts with autonomous Hyperestrogenic stimulation. After menarche, the majority of patients with ovarian GNAS mutation have menstrual disturbances and infertility. Objectives We wanted to focus on the fertility of MAS females and propose an appropriate management, by a detailed case report and an exhaustive review of the literature on fertility and pregnancy in MAS females. Results We present the case of a 29-year-old MAS female, who…
Naevus épidermique cérébriforme associé à FGFR2 : élargissement du spectre du naevus sébacé papillomateux et pédonculé
Introduction Des mutations postzygotiques de FGFR2 ont ete identifiees dans des formes d’acne en mosaique, dans le naevus epidermique keratinocytaire, l’acanthosis nigricans naevoide ou RAVEN (rounded and velvety epidermal nevus) et le naevus sebace papillomateux et pedoncule (NSPP) [1] . Objectifs Determiner les caracteristiques cliniques et genetiques du NSPP et d’une forme de naevus epidermique cerebriforme (NEC), proches sur le plan clinique. Patients et methodes Nourrissons diagnostiques avec des NSPP et NEC sur une periode de 10 ans (2010-2019) dans deux centres de dermatologie pediatrique en Suisse et en France. Les caracteristiques cliniques et histologiques ont ete evaluees. Le seq…
Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects
International audience; KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had a…
Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation
Abstract The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomali…
Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases.
Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 muta…
Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity
PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.RESULTS: We identified 13 individuals with heterozygous…
Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature.
X-linked intellectual disability (XLID) is a genetically heterogeneous condition involving more than 100 genes. To date, 35 pathogenic variants have been reported in the lysine specific demethylase 5C (KDM5C) gene. KDM5C variants are one of the major causes of moderate to severe XLID. Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity. For most of these variants, related female carriers have been reported, but phenotypic descriptions were poor. Here, we present clinical and molecular features of 19 females carrying 10 novel heterozygous variants affecting KDM5C function, including five probands with de novo variants. Four h…
Kosaki overgrowth syndrome: A novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications
Heterozygous activating variants in platelet-derived growth factor, beta (PDGFRB) are associated with phenotypes including Kosaki overgrowth syndrome (KOGS), Penttinen syndrome and infantile myofibromatosis (IM). Here, we present three new cases of KOGS, including a patient with a novel de novo variant c.1477A > T p.(Ser493Cys), and the oldest known individual age 53 years. The KOGS phenotype includes characteristic facial features, tall stature, scoliosis, hyperelastic thin skin, lipodystrophy, variable intellectual and neurological deterioration, and abnormalities on brain imaging. Long-term outcome is unknown. Our cases confirm the phenotypic spectrum includes progressive flexion contrac…
Pourquoi et comment rechercher les anomalies chromosomiques et les mutations ponctuelles post-zygotiques dans les dyschromies cutanées en mosaïque
Introduction La determination de l’etiologie genetique des anomalies de la pigmentation cutanee en mosaique est un enjeu a double titre: d’une part, elle necessite des methodes adaptees a la detection de variations genetiques a faible taux et confinees au tissu atteint, et d’autre part elle est un element d’orientation determinant pour la prise en charge des patients (mise en evidence d’une cible therapeutique, etablissement de la strategie de surveillance, conseil genetique). Le sequencage d’exome (ES) est en 2019 la methode de reference pour la detection des mutations ponctuelles post-zygotiques (mSNV), mais la detection d’anomalies chromosomiques en mosaique (mCNV) repose habituellement …
Expanding the clinical spectrum of mosaic BRAF skin phenotypes
BRAF postzygotic activating mutations have been found in 50% of cases of syringocystadenoma papilliferum (SCAP)1 and in phacomatosis pigmentokeratotica (PPK)2,3 , also possibly caused by HRAS4 mutations. BRAF is a RAS-activating serine/threonine kinase of the MAP kinase pathway, resulting in cell growth and proliferation. BRAF mutations, particularly p.(Val600Glu), are frequently identified in melanoma and other human cancers5 . We report clinical presentations of three patients with postzygotic BRAF mutations in affected skin, identified by next generation sequencing (NGS).
Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway
To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K-AKT-mTOR signaling pathway.We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K-AKT-mTOR pathway genes by next-generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid.During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the…
Interest of exome sequencing trio-like strategy based on pooled parental DNA for diagnosis and translational research in rare diseases.
Abstract Background Exome sequencing (ES) has become the most powerful and cost‐effective molecular tool for deciphering rare diseases with a diagnostic yield approaching 30%–40% in solo‐ES and 50% in trio‐ES. We applied an innovative parental DNA pooling method to reduce the parental sequencing cost while maintaining the diagnostic yield of trio‐ES. Methods We pooled six (Agilent‐CRE‐v2–100X) or five parental DNA (TWIST‐HCE–70X) aiming to detect allelic balance around 8–10% for heterozygous status. The strategies were applied as second‐tier (74 individuals after negative solo‐ES) and first‐tier approaches (324 individuals without previous ES). Results The allelic balance of parental‐pool v…
Molecular diagnosis of PIK3CA-related overgrowth spectrum (PROS) in 162 patients and recommendations for genetic testing.
Postzygotic activating mutations of PIK3CA cause a wide range of mosaic disorders collectively referred to as PIK3CA-related overgrowth spectrum (PROS). We describe the diagnostic yield and characteristics of PIK3CA sequencing in PROS. We performed ultradeep next-generation sequencing (NGS) of PIK3CA in various tissues from 162 patients referred to our clinical laboratory and assessed diagnostic yield by phenotype and tissue tested. We identified disease-causing mutations in 66.7% (108/162) of patients, with mutant allele levels as low as 1%. The diagnostic rate was higher (74%) in syndromic than in isolated cases (35.5%; P = 9.03 × 10−5). We identified 40 different mutations and found stro…
Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes
PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074-3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non-compaction (LVNC) with a PRDM16 variant. The third-trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non-compaction of the myocardium of the left ventricle. Exom…
Genomic characterization of mosaic cutaneous pigmentary disorders
Ntroduction: Mosaic cutaneous dyschromia is strongly evocative of an underlying genetic mosaicism. These post-zygotic events are challenging for conventional diagnostic tools. Thus, genetic basis of mosaic cutaneous dyschromia still remained poorly understood. Materials and Methods: The M.U.S.T.A.R.D. cohort gathers DNA from skin biopsies of patients with mosaic cutaneous dyschromia. After a specialised phenotype analysis, they are referred to either trio exome sequencing (ES) at 200X, or targeted ultra-deep sequencing (60,000X) of candidate genes. Data are analysed with a tailored pipeline, allowing detection of both low-rate nucleotidic variations or chromosomal events. Results: From 2013…