Search results for "Haploinsufficiency"
showing 10 items of 54 documents
Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency
2020
International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various ty…
EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder
2021
International audience; Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We…
Haploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomalies
2015
Background— Adams–Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. Methods and Results— Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregat…
Proteomic signature of the Dravet syndrome in the genetic Scn1a-A1783V mouse model.
2021
Abstract Background Dravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course. Methods A knock-in mouse model of Dravet syndrome with Scn1a haploinsufficiency was used for whole proteome, seizure, and behavioral analysis. Hippocampal tissue was dissected from two- (prior to epilepsy manifestation) and four- (following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantificati…
Mandibular-pelvic-patellar syndrome (mpp) is a novel pitx1-related disorder due to alteration of pitx1 transactivation ability
2020
International audience; PITX1 is a homeobox transcription factor essential for hindlimb morphogenesis. Two PITX1-related human disorders have been reported to date: PITX1 ectopic expression causes Liebenberg syndrome, characterized by malformation of upper limbs showing a "lower limb" appearance; PITX1 deletions or missense variation cause a syndromic picture including clubfoot, tibial hemimelia, and preaxial polydactyly. We report two novel PITX1 missense variants, altering PITX1 transactivation ability, in three individuals from two unrelated families showing a distinct recognizable autosomal dominant syndrome, including first branchial arch, pelvic, patellar, and male genital abnormaliti…
2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment.
2015
Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have …
Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.
2003
Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries(1,2). About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache(3). Although the mode of transmission is controversial(4), population-based and twin studies have implicated genetic factors, especially in migraine with aura(5,6). Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of t…
Haploinsufficiency of 16.4 Mb from chromosome 22pter-q11.21 in a girl with unilateral conductive hearing loss.
2009
We present the postnatal diagnosis of a de novo der(18)t(18;22)(p11.32;q11.21)pat, resulting in an unbalanced 45,XX,der (18)t(18;22) karyotype in a girl with conductive hearing loss on the left and ptosis of the right upper eye-lid. Unilateral ptosis was also observed in the patient’s 2 years and 8 months younger sister, who grows noticeably faster and appears to be a much quicker learner. After speech therapy the patient was eventually placed in normal school. The haploinsufficient 16.4-Mb region on chromosome 22pter→q11.21 contains 10 genes as well as many predicted genes, pseudogenes, and retrotransposed sequences with unknown functions. This observation may prove useful for prenatal dia…
HSP70, the Key to Account for Erythroid Tropism of Diamond-Blackfan Anemia?
2015
Abstract Diamond-Blackfan anemia (DBA) was the first ribosomopathy identified and is characterized by a moderate to severe, usually macrocytic aregenerative anemia associated with congenital malformations in 50% of the DBA cases. This congenital rare erythroblastopenia is due to a blockade in erythroid differentiation between the BFU-e and CFU-e stages. The link between a haploinsufficiency in a ribosomal protein (RP) gene that now encompass 15 different RP genes and the erythroid defect is still to be fully defined. Recently, mutations in TSR2 and GATA1 genes have been identified in a few DBA families. The GATA1 gene encodes for the major transcription factor critical for erythropoiesis an…
GH successful treatment in a female with a de novo 46,XX,add(X)(p36),t(X;Y)(p36.3;p11.2), growth impairment and SHOX-haploinsufficiency
2019
Abstract Children with chromosome translocations, concerning X chromosome, have a genetic pattern different from Turner syndrome; however, when a translocation involves the of part of X chromosome including short stature homeobox-containing Sex-determining Region Y gene, growth may be severely compromised. We describe the clinical case of a 2.2-year-old-female, arrived at our paediatric unit for a decrease of height velocity. The karyotype was 46,XX,add(X)(p36.3). Array comparative genomic hybridization showed a fragment of Y chromosome, extended from 8.803.981 (Yp11.2) to 28.767.604 (Yq11.23). The final karyotype was 46,XX,add(X)(p36),t(X;Y)(p36.3;p11.2). Fluorescence in situ Hybridization…