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

A small de novo 16q24.1 duplication in a woman with severe clinical features.

International audienceWe report here a de novo 16q24.1 interstitial duplication in a woman with a severe phenotype consistent with mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched palate, malar hypoplasia, little subcutaneous fat and arachnodactyly. Although conventional karyotyping was found to be normal, array-CGH detected a small duplication on chromosome 16. Using QFM-PCR, we characterised its proximal and distal breakpoints. The duplication, which is approximately 250 kb, encompasses seven genes (KIAA0182, GINS2, c16orf74, COX4NB, COX4I1, MIR1910 and IRF8). Several reports have previously described large 16q duplications, and some of these overlap with our region in 16q24.1. Due to the variability of the described phenotypes, the characterisation of small 16q duplications may help to determine critical regions and the genes they contain that are associated with the components of complex phenotypes

Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants

Abstract The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity

Joint involvement in Noonan syndrome. A retrospective paediatric descriptive study

International audienceNoonan syndrome is a rare genetic disorder characterized mainly by congenital heart disease, occasional intellectual disability, and varied orthopaedic, rheumatological and haematologic anomalies. Despite potentially serious functional consequences, joint involvement has been rarely studied in the literature. Our objective was to perform a retrospective study evaluating the prevalence and characteristics of joint involvement in Noonan syndrome

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations

tle:4b4b4c39-7aef-44fc-af5e-e13cd0b00e69:afee126f-04b2-41a9-a6dd-b29b7c6c20ab:1Background: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with mono- and bi-allelic pathogenic variants in RBP4, encoding a serum retinol specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). Method: We report here 7 new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, to whom we performed biochemical analyses. Results: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypic expression in dominant forms suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that RBP blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. Conclusion: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients

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Cohorte française de 41 patients porteurs d’une délétion 2q37

International audienceLe locus 2q37 est l’une des régions subtélomériques les plus fréquemment délétées, pouvant être à l’origine du syndrome microdélétionnel 2q37, aussi appelé syndrome d’Ostéodystrophie Héréditaire d’Albright-like (AHO-like) ou syndrome retard mental-brachydactylie (BDMR) (MIM 60043), d’expression clinique variable. Suite à un appel à collaboration nationale, 41 patients porteurs d’une délétion 2q37 isolée ont été recensés. Tous les diagnostics ont été posés par l’analyse chromosomique sur puces à ADN, et confirmés par FISH avec une sonde locus-spécifique 2q37. Les délétions sont de taille variable, de 14kb intragénique DIS3L2 à 9.6 Mb. La majorité des cas est non héritée, de probable survenue de novo. Cette cohorte, pédiatrique et adulte, permet de confirmer la variabilité phénotypique et d’affiner le phénotype post-natal (1 seul cas prénatal). Les deux signes principaux mais inconstants sont les difficultés légères à modérées des apprentissages associées à des troubles comportementaux notamment des difficultés attentionnelles, et la brachydactylie. La morphologie faciale typique précédemment rapportée est fréquente également dans notre cohorte. L’obésité (6/26), le surpoids (3/26), la petite taille (2/29) sont absents dans plus de 70% des cas. L’épilepsie est décrite dans 15% des cas. Les malformations sont le plus souvent cardiaques et rénales, de bon pronostic. D’autres particularités cliniques ont été soulignées (notamment malformations cérébrales non spécifiques, troubles du transit, trouble du sommeil, troubles squelettiques et hyperlaxité). Il s’agit de la plus grosse cohorte de patients non publiés (28/41) décrite à ce jour