Studies on the Cobalt Deficiency in Ruminants (III) : Effects of Thiamine, Glucose and Cobalamin Injection on the Metabolism of Cobalt-deficient Sheep

International audienceN-terminal acetylation is a common protein modification in eukaryotes associated with numerous cellular processes. Inherited mutations in NAA10, encoding the catalytic subunit of the major N-terminal acetylation complex NatA have been associated with diverse, syndromic X-linked recessive disorders, whereas de novo missense mutations have been reported in one male and one female individual with severe intellectual disability but otherwise unspecific phenotypes. Thus, the full genetic and clinical spectrum of NAA10 deficiency is yet to be delineated. We identified three different novel and one known missense mutation in NAA10, de novo in 11 females, and due to maternal germ line mosaicism in another girl and her more severely affected and deceased brother. In vitro enzymatic assays for the novel, recurrent mutations p.(Arg83Cys) and p.(Phe128Leu) revealed reduced catalytic activity. X-inactivation was random in five females. The core phenotype of X-linked NAA10-related N-terminal-acetyltransferase deficiency in both males and females includes developmental delay, severe intellectual disability, postnatal growth failure with severe microcephaly, and skeletal or cardiac anomalies. Genotype–phenotype correlations within and between both genders are complex and may include various factors such as location and nature of mutations, enzymatic stability and activity, and X-inactivation in females

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity

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. International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy

De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits:report of 25 new individuals and review of the literature

TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Etude clinique et moléculaire de 320 enfants atteints d'un syndrome de Marfan ou d'une fibrillinopathie de type 1 parmi une cohorte de 1013 probants porteurs d'une mutation FBN1

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact de la composition des formules d'acides aminés sur le statut nutritionnel d'une cohorte de 77 patients phénylcétonuriques (résultats d'une étude prospective observationnelle réalisée dans le centre de référence des maladies héréditaires et du métabolisme de Nancy)

Résumé françaisDIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Autosomal recessive truncating MAB21L1 mutation associated with a syndromic scrotal agenesis

International audienceWe report on a boy with a rare malformative association of scrotum agenesis, ophthalmological anomalies, cerebellar malformation, facial dysmorphism and global development delay. The reported patient was carrying a homozygous frameshift in MAB21L1 detected by whole-exome sequencing, considered as the most likely disease-causing variant. Mab21l1 knockout mice present a strikingly similar malformative association of ophthalmological malformations of the anterior chamber and preputial glands hypoplasia. We hypothesize that MAB21L1 haploinsufficiency cause a previously undescribed syndrome with scrotal agenesis, ophthalmological anomalies, facial dysmorphism and gross psychomotor delay as remarkable hallmarks. Four cases from the literature were reported with features suggestive of a similar and recognizable clinical entity. We hypothesize that MAB21L1 should be the culprit gene in these patients

Novel missense mutations in PRPF6 cause autosomal dominant retinitis pigmentosa with incomplete penetrance and impairment of PRPF6 protein localization within the nucleus

International audiencePurpose : To characterize clinically and genetically two families with autosomal dominant retinitis pigmentosa (adRP) with new causative mutations in PRPF6, a gene described to be associated with this condition in a single study.Methods : A large adRP and sporadic RP cohort was screened for mutations using targeted next-generation sequencing. Clinical investigations included visual acuity and visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, full-fields and multifocal electroretinogram (ERG) recording. Cellular localization of GFP-tagged wild-type or mutated PRPF6 in HEK293 transfected cells was observed by confocal microscopy.Results : Two heterozygous mutations c.680C>T (p.Thr227Met) and c.514C>T (p.Arg172Trp) in PRPF6 were identified in an adRP family and in a sporadic RP patient, respectively. Both variants segregated with the disease phenotype and were predicted to be pathogenic. An asymptomatic heterozygous carrier of the p.Arg172Trp mutation was also identified. In HEK293 transfected cells, an abnormal accumulation of the two mutated GFP-PRPF6, but not wild-type, within Cajal bodies was observed.Conclusions : We identified two novel causative mutations in PRPF6, responsible for autosomal dominant retinitis pigmentosa with variation of penetrance. Presence of asymptomatic carriers is common among patients with adRP, especially when the cause of the disease is due to a mutation in splicing factors’ genes. The two mutations identified lead to a mislocalization of the PRPF6 protein within the nucleus, which could indicate a possible alteration in the assembly or recycling of the tri-snRNP complex of the spliceosome

Novel missense mutations in PRPF6 cause autosomal dominant retinitis pigmentosa with incomplete penetrance and impairment of PRPF6 protein localization within the nucleus

International audiencePurpose : To characterize clinically and genetically two families with autosomal dominant retinitis pigmentosa (adRP) with new causative mutations in PRPF6, a gene described to be associated with this condition in a single study.Methods : A large adRP and sporadic RP cohort was screened for mutations using targeted next-generation sequencing. Clinical investigations included visual acuity and visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, full-fields and multifocal electroretinogram (ERG) recording. Cellular localization of GFP-tagged wild-type or mutated PRPF6 in HEK293 transfected cells was observed by confocal microscopy.Results : Two heterozygous mutations c.680C>T (p.Thr227Met) and c.514C>T (p.Arg172Trp) in PRPF6 were identified in an adRP family and in a sporadic RP patient, respectively. Both variants segregated with the disease phenotype and were predicted to be pathogenic. An asymptomatic heterozygous carrier of the p.Arg172Trp mutation was also identified. In HEK293 transfected cells, an abnormal accumulation of the two mutated GFP-PRPF6, but not wild-type, within Cajal bodies was observed.Conclusions : We identified two novel causative mutations in PRPF6, responsible for autosomal dominant retinitis pigmentosa with variation of penetrance. Presence of asymptomatic carriers is common among patients with adRP, especially when the cause of the disease is due to a mutation in splicing factors’ genes. The two mutations identified lead to a mislocalization of the PRPF6 protein within the nucleus, which could indicate a possible alteration in the assembly or recycling of the tri-snRNP complex of the spliceosome