Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data ...of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients’ lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.
Le syndrome cérébrofrontofacial de Baraitser-Winter (BWS) est rare et concerne 100 cas dans le monde. Le phénotype clinique est variable, caractérisé principalement par : dysmorphie faciale, ...colobome, surdité, anomalies rénales, pachygyrie et épilepsie.
Il s’agit d’un jeune homme âgé de 18 ans, atteint du syndrome BWS. À l’examen physique, on note un excès de peau sur le cou, des oreilles basses, un hypertélorisme, un thorax étroit, une clinodactylie bilatérale des Ve doigts, une bifidité rénale bilatérale, une dystrophie papillaire bilatérale. Il a été mis en évidence un variant pathogène hétérozygote de novo : c.224T>C ; p.ILE75THR dans le gène ACTB (NM_001101.5). L’histoire récente débute à l’âge de 18 ans avec un syndrome catatonique aigu avec raideur marquée des quatre membres, après avoir reçu du métoclopramide dans le cadre d’une virose. L’IRM cérébrale, le PET scan et le DAT scan sont revenus normaux. Le patient a reçu une administration de chlorhydrate de tropatépine qui a amélioré le syndrome catatonique et a permis au patient de retrouver son autonomie et de marcher seul. Devant la persistance de la bradykinésie, et de la rigidité des membres supérieurs une dopathérapie à doses progressives a été instaurée. L’état du patient s’est progressivement amélioré jusqu’à arrêt au bout de 6 mois de la dothérapie.
Il s’agit du premier patient atteint du syndrome de BWCFF ayant présenté des signes extra-pyramidaux. Jusqu’alors ces symptômes n’étaient présents que dans le syndrome de dystonie-surdité apparenté ne concernant pas la même mutation génétique. Ces deux tableaux cliniques diffèrent par l’âge de début, le mode d’installation, la symptomatologie et la dopa-sensibilité.
Ce tableau génotype-phénotype expand le spectre du syndrome de Baraitser Winter avec pour la première fois des symptômes de la lignée extra-pyramidale.
Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and ...congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The
and
genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely,
,
,
,
,
and
. They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways.
The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC.
Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in
(77.8%),
(6.7%),
(2.2%),
(2.2%) or
(2.2%). No distinctive feature was remarkable of a specific genotype-phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in
of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences.
We confirmed that
and
are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).
Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe ...intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow‐up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next‐generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.
Objective
We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.
Methods
We ...retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams‐Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.
Results
40 fetuses with WBS were collected and the most common features were intra‐uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.
Conclusion
This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.
Key points
What is already known on this topic?
Deletion of the 7q11.23 region causes the Williams Beuren syndrome (WBS). The reciprocal duplication is responsible for a distinctive although less severe neurodevelopmental disorder.
Diagnosis of WBS is usually suspected postnatally in infants but its prenatal presentation remains challenging.
What does this study add?
Largest series of fetuses with a 7q11.23 deletion or a 7q11.23 duplication.
Antenatal ultrasound findings of prenatal 7q11.23 copy number variations.
Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare ...autosomal recessive condition presenting with severe pre‐ and post‐natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver‐Russell syndrome. We report here three patients in two distinct non‐Finnish families from North France who were first suspected to have Silver–Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non‐Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.
One flue over the cuckoo's nest: A novel porous Zr‐based MOF combining a high chemical stability, easy “green” synthesis and scalability is prepared. This material incorporating carboxylic functions ...on its organic linkers has thermodynamically and kinetically very promising properties for CO2 capture from post‐combustion flue gas under real working conditions.
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