CHARGE syndrome: an update SANLAVILLE, Damien; VERLOES, Alain
European journal of human genetics,
04/2007, Letnik:
15, Številka:
4
Journal Article
Recenzirano
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CHARGE syndrome is a rare, usually sporadic autosomal dominant disorder due in 2/3 of cases to mutations within the CHD7 gene. The clinical definition has evolved with time. The 3C triad ...(Coloboma-Choanal atresia-abnormal semicircular Canals), arhinencephaly and rhombencephalic dysfunctions are now considered the most important and constant clues to the diagnosis. We will discuss here recent aspects of the phenotypic delineation of CHARGE syndrome and highlight the role of CHD7 in its pathogeny. We review available data on its molecular pathology as well as cytogenetic and molecular evidences for genetic heterogeneity within CHARGE syndrome.
Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, ...microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype–phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype–genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4‐year‐old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.
6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were ...associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.
ObjectivesThe aim of this study was to describe the epidemiology of infantile Pompe disease (IPD) in French Guiana, a French overseas territory, by combining a retrospective case records study and a ...prospective anonymous genotyping in a sample of mothers followed in the two major maternity units of French Guiana.MethodsWe identified 19 newborns with IPD born within a 13-year-period in French Guiana, corresponding to 1/4528 births. All children were born within the African-American Maroon (Bushinengue) community originating from slaves who settled along the Maroni river in the 19th century. We also performed an anonymised screening for all women in postpartum, in the two main maternity units of French Guiana.ResultsGenetic investigations revealed that all patients with IPD were homozygotes or compound heterozygotes for two known pathogenic variations: c.2560C>T p.(Arg854*) that has already been reported in African-Americans and c.1942G>A p.(Gly648Ser), a rare previously considered to be variant. We identified no heterozygotes among 453 mothers of various ethnicities in Cayenne, but 15 heterozygotes among 425 mothers (1/27) in Saint-Laurent-du-Maroni (95% CI 1/45 to 1/17), all from the Maroon community, which corresponds to an expected IPD incidence in Maroons of 1/1727 (95% CI 1/1156 to 1/8100).ConclusionThe incidence of IPD in the Maroon community is roughly 50 times higher than elsewhere in the world. The presence of only two different variants in all affected patients is compatible with a double founder effect in a relatively small population that has seldom mixed with other regional populations in the past and therefore has a reduced pool of genotypes.
Abstract Background 15q11-q13 region is an area of well-known susceptibility to genomic rearrangements, in which several breakpoints have been identified (BP1–BP5). Duplication of this region is ...observed in two instances: presence of a supernumerary marker chromosome (SMC) derived of chromosome 15, or interstitial tandem duplication. Duplications are clinically characterized by a variable phenotype that includes central hypotonia, developmental delay, speech delay, seizure, minor dysmorphic features and autism. Methods Retrospective clinical and molecular study of 30 unrelated patients who were identified among the patients seen at the genetic clinics of Robert DEBRE hospital with microduplication of the 15q11-q13 region. Results Fifteen patients presented with a supernumerary marker derived from chromosome 15. In fourteen cases the SMC was of large size, encompassing the Prader–Willi/Angelman critical region. All but one was maternal in origin. One patient had a PWS-like phenotype in absence of maternal UPD. In one case, the marker had a smaller size and contained only the BP1–BP2 region. Fifteen patients presented with interstitial duplication. Four cases were inherited from phenotypically normal parents (3 maternal and 1 paternal). Phenotypic features were somewhat variable and 57% presented with autism. Twelve patients showed cerebral anomalies and 18 patients had an abnormal EEG with a typical, recognizable pattern of excessive diffuse rapid spikes in the waking record, similar to the pattern observed after benzodiazepine exposure. Duplication of paternally expressed genes MKRN3 , MAGEL2 and NDN in two autistic patients without extra material of a neighboring region enhances their likelihood to be genes related to autism.
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