Novel interstitial 2q12.3q13 microdeletion predisposes to developmental delay and behavioral problems

International audienceMicroarray-based comparative genomic hybridization (aCGH) is being increasingly applied to delineate novel genomic disorders and related syndromes in patients with developmental delay. In this study, detailed clinical and cytogenetic data of three unrelated patients with interstitial 2q12.3q13 microdeletion were described and compared with thirteen 2q12.3q13 microdeletion patients, gathered from the medical literature and public databases. 60 K aCGH analysis revealed three overlapping 2q12.3q13 microdeletions measuring 1.88 Mb in patient 1, 1.25 Mb in patient 2, and 0.41 Mb in patient 3, respectively. Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative real-time PCR. Variable clinical features of 2q12.3q13 microdeletion including microcephaly, prenatal growth retardation, developmental delay, short stature, behavioral problems, learning difficulties, skeletal anomalies, congenital heart defects, and features of ectodermal dysplasia were observed. The boundaries and sizes of the 2q12.3q13 deletions in the sixteen patients were different, but an overlapping region of 249 kb in 2q12.3 was defined. The SRO (smallest region of overlap) encompasses four genes, including LIMS1, RANBP2, CCDC138, and EDAR. Among these genes, RANBP2 is a strong candidate gene for neurological phenotype and genetic susceptibility to viral infections. To our knowledge, this is the first published report of 2q12.3q13 microdeletion syndrome and our observations strongly suggest that these recurrent CNVs may be a novel risk factor for developmental delay with variable expressivity and incomplete penetrance

Drivers for primary producers’ dynamics: New insights on annual benthos pelagos monitoring in anthropised freshwater marshes (Charente-Maritime, France)

International audienceWetlands, especially marshes, support many services such as carbon catchment control or water purification led by primary producers such as phytoplankton and microphytobenthos (PB). The impact of the sedimentary compartment, as source and sink of essential nutrients for the water column, is often neglected in the study of their dynamics and water purification capacity of the systems. This work compared monthly (between February 2020 and April 2021) the benthic and pelagic primary producers’ dynamics in two anthropised freshwater marshes (Marans and Genouillé), with the simultaneous follow-up of physico-chemical parameters of the water column and nutrient fluxes at the sediment-water (SWI) interface. It was suggested a strong contribution of phytoplankton (pumping) and the benthic compartment (denitrification) to the water purification of these two nitrates (NO3-)-rich marshes. Total phytoplankton production fluctuated between ~5 (winter) and 1500 mg C m-3 d-1 (fall) at Marans and between 40 (winter) and ~750 mg C m-3 d-1 (spring) at Genouillé. At Marans, soluble reactive phosphorus (SRP) benthic effluxes (-2.101 to -6.102 µmol m-2 d-1 in fall and summer respectively) coincided with phytoplankton bloom periods. These effluxes were inhibited by NO3- penetration in the sediment (0 to 5.104 µmol m-2 d-1), by inhibiting iron respiration. At Genouillé, inhibition of SRP effluxes depended on denitrification rate and on P stocks in the sediment, where slight SRP effluxes (-101 µmol m-2 d-1) could have co-occurred with slight NO3- influxes (5.102 µmol m-2 d-1) in spring. The presence of PB (between 10-60 and 40-120 mg gsed-1 at Marans and Genouillé respectively), suggested a strong contribution of the benthic compartment to the total primary production (benthic and pelagic through resuspension processes) in these environments. This work encourages to consider the benthos and the pelagos as a unicum to provide better sustainable management of such systems and limit eutrophication risks in coastal areas

Pseudodicentric Chromosome Originating from Autosomes 9 and 21 in a Male Patient with Oligozoospermia

International audienceGenetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient

Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients

International audienceWe describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a ‘Gardos channelopathy’. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up

A framework to identify contributing genes in patients with Phelan-McDermid syndrome

International audience[This corrects the article DOI: 10.1038/s41525-017-0035-2.]

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

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

Integrated clinical and omics approach to rare diseases : Novel genes and oligogenic inheritance in holoprosencephaly

Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10 -9). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations