Cordeddu V.,Instituto Superiore Of Sanita |
Redeker B.,University of Amsterdam |
Stellacci E.,Instituto Superiore Of Sanita |
Jongejan A.,University of Amsterdam |
And 21 more authors.
Nature Genetics | Year: 2014
Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism. © 2014 Nature America, Inc.
PubMed | University of Amsterdam, CNR Institute of Neuroscience, Laboratorio Mendel, Swedish University of Agricultural Sciences and 7 more.
Type: Journal Article | Journal: Nature genetics | Year: 2014
Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.
Lepri F.,Laboratorio Mendel |
De Luca A.,Laboratorio Mendel |
Stella L.,University of Rome Tor Vergata |
Rossi C.,UO Genetica Medica |
And 26 more authors.
Human Mutation | Year: 2011
Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. © 2011 Wiley-Liss, Inc.
Di Giacopo R.,University of Trento |
Di Giacopo R.,University Cattolica del sacro CuoreRome |
Cianetti L.,Instituto Superiore Of Sanitarome |
Caputo V.,University La SapienzaRome |
And 15 more authors.
Journal of the Neurological Sciences | Year: 2015
Abstract Objective This work investigated the molecular cause responsible for a late-onset parkinsonism-dystonia phenotype in three Italian siblings, and clinically characterize this condition. Methods Extensive neurophysiological and neuroradiological exams were performed on the three sibs. Most frequent late-onset metabolic diseases were ruled out through laboratory and biochemical analyses. A whole exome sequencing (WES) approach was used to identify the molecular cause underlying this condition. Results and conclusions Peculiar neurologic phenotype was characterized by dystonia-parkinsonism, cognitive impairment, gait ataxia and apraxia, pyramidal signs. WES analysis allowed the identification of a compound heterozygosity for two nucleotide substitutions (c.1340G>A, p.R447H; c.790C>T, p.Q264X) affecting the TPP1 gene in the three affected siblings. Biochemical analyses demonstrated abrogated TPP1 catalytic activity in primary skin fibroblasts, but revealed residual activity in leukocytes. Our findings document that late infantile neuronal ceroid lipofuscinosis (CLN2), which is caused by TPP1 gene mutations, should be considered in the differential diagnosis of autosomal recessive dystonia-parkinsonism syndromes. The availability of enzyme replacement therapy and other therapeutic approaches for ceroid lipofuscinoses emphasizes the value of reaching an early diagnosis in patients with atypical and milder presentation of these disorders. © 2015 Elsevier B.V.
Parri V.,University of Siena |
Katzaki E.,University of Siena |
Uliana V.,University of Siena |
Scionti F.,University of Siena |
And 23 more authors.
European Journal of Human Genetics | Year: 2010
Cohen syndrome is a rare, clinically variable autosomal recessive disorder characterized by mental retardation, postnatal microcephaly, facial dysmorphisms, ocular abnormalities and intermittent neutropenia. Mutations in the COH1 gene have been found in patients from different ethnic origins. However, a high percentage of patients have only one or no mutated allele. To investigate whether COH1 copy number changes account for missed mutations, we used multiplex ligation-dependent probe amplification (MLPA) to test a group of 14 patients with Cohen syndrome. This analysis has allowed us to identify multi-exonic deletions in 11 alleles and duplications in 4 alleles. Considering our previous study, COH1 copy number variations represent 42% of total mutated alleles. To our knowledge, COH1 intragenic duplications have never been reported in Cohen syndrome. The three duplications encompassed exons 4-13, 20-30 and 57-60, respectively. Interestingly, four deletions showed the same exon coverage (exons 6-16) with respect to a deletion recently reported in a large Greek consanguineous family. Haplotype analysis suggested a possible founder effect in the Mediterranean basin. The use of MLPA was therefore crucial in identifying mutated alleles undetected by traditional techniques and in defining the extent of the deletions/duplications. Given the high percentage of identified copy number variations, we suggest that this technique could be used as the initial screening method for molecular diagnosis of Cohen syndrome. © 2010 Macmillan Publishers Limited All rights reserved.
Bukvic N.,University of Foggia |
Delli Carri V.,OORR |
Di Cosola M.L.,UOC Laboratorio Genetica Medica |
Pustorino G.,OORR |
And 10 more authors.
American Journal of Medical Genetics, Part A | Year: 2010
X;Y translocation is a relatively rare event in humans. Analyzed cytogenetically, the majority of these aberrations have breakpoints at Xp22 and Yq11. Females with t(X;Y)(p22;q11) are phenotypically normal except for short stature, while the males may have abnormalities. Aberrations that lead to nullisomy of the deleted region and complete loss of the respective genes have been recognized as a cause of variable contiguous gene syndromes in males. The phenotype depends on the extent and position of the deletion showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism with anosmia, ocular albinism, short stature, and mental retardation. In addition, some patients have been reported with symptoms of attention deficit hyperactivity disorder. The extent of terminal Xp deletions is limited by the presence of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere. The deletions in the majority of viable reported male patients extend to the STS (∼7.0 Mb) or to the KAL1 (∼8.5Mb) loci. We present a clinical, cytogenetic, FISH, and array CGH study of a family with an Xp;Yq translocation. The chromosomal status is also discussed in the light of their phenotypic traits. The final karyotypes of the patients were designated as: Patient 1: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+, Xqter+)mat.arr cghXp22.31p22.33(RP11-60P14→RP13-391G2) x0;arr cgh Yq11.221qter (RP11-235I1→RP11-270H4)x2. Patient 2: 46,X,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+, Xqter+)mat.arr cghXp22.31p22.33(RP11-60P14→RP13-391G2) x1;arr cgh Yq11.221qter (RP11-235I1→RP11-270H4)x1.