Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant

International audienceHoloprosencephaly (HPE) is a clinically and genetically heterogeneous disease, which can be associated with various prenatal comorbidities not always detectable on prenatal ultrasound. We report on the case of a foetus carrying a semi-lobar HPE diagnosed at ultrasound, for which a fetal autopsy and a whole exome sequencing were performed following a medical termination of pregnancy. Neuropathological examination confirmed the semi-lobar HPE and general autopsy disclosed a total pancreas agenesis. Whole exome sequencing found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo in the foetus. The same variant was previously reported in 5 unrelated children. All individuals had HPE, and 4 out of 5 presented endo- and exocrine pancreatic insufficiency or total pancreas agenesis. CNOT1 encodes a subunit of the CCRN4-NOT complex, expressed at the early stage of embryonic development. This report is the first fetal description of the phenotype associating HPE and pancreatic agenesis linked to the recurrent CNOT1 missense c.1603C>T, p.(Arg535Cys). This finding strengthens the hypothesis of a specific recurrent variant associated with a particular phenotype of HPE and pancreas agenesis. The fetal autopsy that revealed the pancreas agenesis was crucial in guiding the genetic diagnosis and enabling accurate genetic counselling

Scarcity of available information resources for patients and clinicians after a diagnosis of ultra-rare diseases: retrospective on a cohort of 626 individuals with congenital abnormalities and/or intellectual disability

International audienceMeeting Abstract P23.046.

Scarcity of available information resources for patients and clinicians after a diagnosis of ultra-rare diseases: retrospective on a cohort of 626 individuals with congenital abnormalities and/or intellectual disability

International audienceMeeting Abstract P23.046.

Genetics of neural tube defects: new candidate genes and complex mode of inheritance

International audienc

ATP7A mutation with occipital horns and distal motor neuropathy: A continuum

International audienceATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489) (Kennerson et al., 2010). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein (Møller, 2015). Thus far OHS and SMAX3 only partially overlap. In fact patients with OHS usually have no distal motor neuropathy signs but, on the other hand, occipital horns, which are the main sign of OHS, have not been described in SMAX3 patient. We describe here a patient bearing a missense ATP7A mutation with associated signs of distal motor neuropathy as well as occipital horns, confirming that OHS and SMAX3 are a continuum

Inversion duplication deletions involving the long arm of chromosome 13: phenotypic description of additional three fetuses and genotype-phenotype correlation.

International audienceInversion duplication and terminal deletion of the long arm of chromosome 13 (inv dup del 13q) is a rare chromosomal rearrangement: only five patients have been reported, mostly involving a ring chromosome 13. We report on additional three fetuses with pure inv dup del 13q: Patient 1 had macrosomia, enlarged kidneys, hypersegmented lungs, unilateral moderate ventriculomegaly, and a mild form of hand and feet preaxial polydactyly; Patient 2 had intrauterine growth retardation, widely spaced eyes, left microphthalmia, right anophthalmia, short nose, bilateral absent thumbs, cutaneous syndactyly of toes 4 and 5, bifid third metacarpal, a small left kidney, hyposegmented lungs, and partial agenesis of the corpus callosum; Patient 3 had widely spaced eyes, long and smooth philtrum, low-set ears, median notch in the upper alveolar ridge, bifid tongue, cutaneous syndactyly of toes 2 and 3, enlarged kidneys and pancreas, arhinencephaly, and partial agenesis of the corpus callosum. We compared the phenotypes of these patients to those previously reported for ring chromosome 13, pure 13q deletions and duplications. We narrowed some critical regions previously reported for lung, kidney and fetal growth, and for thumb, cerebral, and eye anomalies

LIS1-Related Isolated Lissencephaly: Spectrum of Mutations and Relationships With Malformation Severity

International audienceObjective: With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype.Design: Retrospective study.Subjects: A total of 63 patients with posteriorly predominant lissencephaly.Interventions: Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined.Results: Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly.Conclusion: Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

Purpose: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation. Methods: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine–based classifier distinguishing CDK13-RD and non–CDK13-RD samples. Results: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance. Conclusion: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder