%0 Journal Article %J J Paediatr Child Health %D 2018 %T Afebrile seizures in infants: Never forget magnesium! %A Minute, Marta %A Ventura, Giovanna %A Giorgi, Rita %A Faletra, Flavio %A Costa, Paola %A Cozzi, Giorgio %B J Paediatr Child Health %V 54 %P 446-448 %8 2018 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29411453?dopt=Abstract %R 10.1111/jpc.13854 %0 Journal Article %J Am J Med Genet A %D 2017 %T Phenotypic expression of 19q13.32 microdeletions: Report of a new patient and review of the literature. %A Travan, Laura %A Naviglio, Samuele %A De Cunto, Angela %A Pellegrin, Andrea %A Pecile, Vanna %A Spinelli, Alessandro Mauro %A Cappellani, Stefania %A Faletra, Flavio %X

The phenotypic manifestations of microdeletions in the 19q13.32 region are still poorly known. In this paper we report a patient who presented with hypotonia, developmental delay, facial dysmorphism, micrognathia, kyphoscoliosis, and buried penis. Chromosomal microarray revealed an interstitial 327 kb de novo microdeletion in the 19q13.32 region comprising eight genes (ARGHAP35, NPAS1, TMEM160, ZC3H4, SAE1, BBC3, MIR3190, and MIR3191). Previously reported cases of microdeletions in the 19q13.32 region were reviewed and compared to our patient, highlighting the common features of a possible 19q13.32 microdeletion syndrome.

%B Am J Med Genet A %8 2017 Apr 14 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28411391?dopt=Abstract %R 10.1002/ajmg.a.38256 %0 Journal Article %J J Ultrasound Med %D 2016 %T A Case of Prenatal Neurocytoma Associated With ATR-16 Syndrome. %A Quadrifoglio, Mariachiara %A Faletra, Flavio %A Bussani, Rossana %A Pecile, Vanna %A Zennaro, Floriana %A Grasso, Alessandra %A Zandonà, Lorenzo %A Alberico, Salvatore %A Stampalija, Tamara %B J Ultrasound Med %V 35 %P 1359-61 %8 2016 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/27235459?dopt=Abstract %R 10.7863/ultra.15.07045 %0 Journal Article %J Clin Immunol %D 2015 %T Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. %A Lougaris, Vassilios %A Faletra, Flavio %A Lanzi, Gaetana %A Vozzi, Diego %A Marcuzzi, Annalisa %A Valencic, Erica %A Piscianz, Elisa %A Bianco, AnnaMonica %A Girardelli, Martina %A Baronio, Manuela %A Loganes, Claudia %A Fasth, Anders %A Salvini, Filippo %A Trizzino, Antonino %A Moratto, Daniele %A Facchetti, Fabio %A Giliani, Silvia %A Plebani, Alessandro %A Tommasini, Alberto %K B-Lymphocytes %K Child, Preschool %K Female %K Germinal Center %K Humans %K Hyper-IgM Immunodeficiency Syndrome %K Infant %K Male %K Mutation %K Phenotype %K Phosphatidylinositol 3-Kinases %K RNA Splice Sites %K Sequence Analysis, DNA %B Clin Immunol %V 159 %P 33-6 %8 2015 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25939554?dopt=Abstract %R 10.1016/j.clim.2015.04.014 %0 Journal Article %J J Pediatr %D 2015 %T "Blaschkoid dyspigmentation" in a child: don't forget fibroblast chromosomal analysis. %A Gortani, Giulia %A Faletra, Flavio %A Bruno, Irene %A Berti, Irene %A Ventura, Alessandro %K Abnormalities, Multiple %K Child, Preschool %K Chromosomes %K DNA %K Female %K Fibroblasts %K Humans %K Phenotype %K Pigmentation Disorders %B J Pediatr %V 166 %P 490-90.e1 %8 2015 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25433905?dopt=Abstract %R 10.1016/j.jpeds.2014.10.028 %0 Journal Article %J J Pediatr %D 2015 %T A brain and heart connection: X-linked periventricular heterotopia. %A Naviglio, Samuele %A Bruno, Irene %A Zanus, Caterina %A Faletra, Flavio %A Ventura, Alessandro %K Adolescent %K Brain %K Diagnosis, Differential %K DNA Mutational Analysis %K Epilepsy %K Female %K Filamins %K Humans %K Magnetic Resonance Imaging %K Mutation %K Periventricular Nodular Heterotopia %B J Pediatr %V 166 %P 776 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25557968?dopt=Abstract %R 10.1016/j.jpeds.2014.11.037 %0 Journal Article %J World J Pediatr %D 2015 %T Genetic analysis of Italian patients with congenital tufting enteropathy. %A d'Apolito, Maria %A Pisanelli, Daniela %A Faletra, Flavio %A Giardino, Ida %A Gigante, Maddalena %A Pettoello-Mantovani, Massimo %A Goulet, Olivier %A Gasparini, Paolo %A Campanozzi, Angelo %X

BACKGROUND: Congenital tufting enteropathy (CTE), an inherited autosomal recessive rare disease, is a severe diarrhea of infancy which is clinically characterized by absence of inflammation and presence of intestinal villous atrophy. Mutations in the EpCAM gene were identified to cause CTE. Recent cases of syndromic tufting enteropathy harboring the SPINT2 (19q13.2) mutation were described.

METHODS: Four CTE Italian patients were clinically and immunohistochemically characterized. Direct DNA sequencing of EpCAM and SPINT2 genes was performed.

RESULTS: All patients were of Italian origin. Three different mutations were detected (p.Asp219Metfs*15, Tyr186Phefs*6 and p.Ile146Asn) in the EpCAM gene; one of them is novel (p.Ile146Asn). Two patients (P1 and P2) showed compound heterozygosity revealing two mutations in separate alleles. A third patient (P3) was heterozygous for only one novel EpCAM missense mutation (p.Ile146Asn). In a syndromic patient (P4), no deleterious EpCAM mutation was found. Additional SPINT2 mutational analysis was performed. P4 showed a homozygous SPINT2 mutation (p.Y163C). No SPINT2 mutation was found in P3. CLDN7 was also evaluated as a candidate gene by mutational screening in P3 but no mutation was identified.

CONCLUSIONS: This study presented a molecular characterization of CTE Italian patients, and identified three mutations in the EpCAM gene and one in the SPINT2 gene. One of EpCAM mutations was novel, therefore increasing the mutational spectrum of allelic variants of the EpCAM gene. Molecular analysis of the SPINT2 gene also allowed us to identify a SPINT2 substitution mutation (c.488A>G) recently found to be associated with syndromic CTE subjects.

%B World J Pediatr %8 2015 Dec 18 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/26684320?dopt=Abstract %R 10.1007/s12519-015-0070-y %0 Journal Article %J Mutat Res %D 2015 %T Target sequencing approach intended to discover new mutations in non-syndromic intellectual disability. %A Morgan, Anna %A Gandin, Ilaria %A Belcaro, Chiara %A Palumbo, Pietro %A Palumbo, Orazio %A Biamino, Elisa %A Dal Col, Valentina %A Laurini, Erik %A Pricl, Sabrina %A Bosco, Paolo %A Carella, Massimo %A Ferrero, Giovanni Battista %A Romano, Corrado %A d'Adamo, Adamo Pio %A Faletra, Flavio %A Vozzi, Diego %X

The technological improvements over the last years made considerable progresses in the knowledge of the etiology of intellectual Disability (ID). However, at present very little is known about the genetic heterogeneity underlying the non-syndromic form of ID (NS-ID). To investigate the genetic basis of NS-ID we analyzed 43 trios and 22 isolated NS-ID patients using a targeted sequencing (TS) approach. 71 NS-ID genes have been selected and sequenced in all subjects. We found putative pathogenic mutations in 7 out of 65 patients. The pathogenic role of mutations was evaluated through sequence comparison and structural analysis was performed to predict the effect of alterations in a 3D computational model through molecular dynamics simulations. Additionally, a deep patient clinical re-evaluation has been performed after the molecular results. This approach allowed us to find novel pathogenic mutations with a detection rate close to 11% in our cohort of patients. This result supports the hypothesis that many NS-ID related genes still remain to be discovered and that NS-ID is a more complex phenotype compared to syndromic form, likely caused by a complex and broad interaction between genes alterations and environment factors.

%B Mutat Res %V 781 %P 32-6 %8 2015 Nov %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26411299?dopt=Abstract %R 10.1016/j.mrfmmm.2015.09.002 %0 Journal Article %J Mol Med Rep %D 2015 %T Two‑gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results. %A Bianco, Anna Monica %A Faletra, Flavio %A Vozzi, Diego %A Girardelli, Martina %A Knowles, Alessandra %A Tommasini, Alberto %A Zauli, Giorgio %A Marcuzzi, Annalisa %X

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X‑chromosome inactivation (XCI) studies on the patient's mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 µg/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient's mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X‑linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

%B Mol Med Rep %V 12 %P 6128-32 %8 2015 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26300074?dopt=Abstract %R 10.3892/mmr.2015.4215 %0 Journal Article %J Am J Med Genet A %D 2014 %T Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene. %A Faletra, Flavio %A d'Adamo, Adamo P %A Bruno, Irene %A Athanasakis, Emmanouil %A Biskup, Saskia %A Esposito, Laura %A Gasparini, Paolo %K Adolescent %K Arthritis %K Bone and Bones %K Child %K Child, Preschool %K Collagen Diseases %K Collagen Type IX %K Connective Tissue Diseases %K DNA Mutational Analysis %K Facies %K Female %K Genes, Recessive %K Hearing Loss %K Hearing Loss, Sensorineural %K Homozygote %K Humans %K Male %K Mutation %K Pedigree %K Retinal Detachment %X

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

%B Am J Med Genet A %V 164A %P 42-7 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24273071?dopt=Abstract %R 10.1002/ajmg.a.36165 %0 Journal Article %J J Pediatr %D 2014 %T A girl with photosensitivity and hepatic steatosis. %A Pavan, Matteo %A Gortani, Giulia %A Rubinato, Elisa %A Faletra, Flavio %A Pastore, Serena %A Ventura, Alessandro %K Child %K Diagnosis, Differential %K Fatty Liver %K Female %K Humans %K Photosensitivity Disorders %K Protoporphyria, Erythropoietic %B J Pediatr %V 165 %P 201-201.e1 %8 2014 Jul %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24704299?dopt=Abstract %R 10.1016/j.jpeds.2014.02.056 %0 Journal Article %J Arch Dis Child Fetal Neonatal Ed %D 2014 %T A neonate with a 'milky' blood. What can it be? %A Bordugo, Andrea %A Carlin, Eva %A Demarini, Sergio %A Faletra, Flavio %A Colonna, Franco %K Female %K Humans %K Hyperlipoproteinemia Type IV %K Infant, Newborn %K Lipoprotein Lipase %K Milk Proteins %K Mutation %B Arch Dis Child Fetal Neonatal Ed %V 99 %P F514 %8 2014 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24747307?dopt=Abstract %R 10.1136/archdischild-2014-305940 %0 Journal Article %J Am J Med Genet A %D 2014 %T Next generation sequencing in nonsyndromic intellectual disability: from a negative molecular karyotype to a possible causative mutation detection. %A Athanasakis, Emmanouil %A Licastro, Danilo %A Faletra, Flavio %A Fabretto, Antonella %A Dipresa, Savina %A Vozzi, Diego %A Morgan, Anna %A d'Adamo, Adamo P %A Pecile, Vanna %A Biarnés, Xevi %A Gasparini, Paolo %K Computational Biology %K Exome %K Female %K Genes, Recessive %K Genes, X-Linked %K Genome-Wide Association Study %K High-Throughput Nucleotide Sequencing %K Humans %K Intellectual Disability %K Karyotype %K Male %K Mutation %K Workflow %X

The identification of causes underlying intellectual disability (ID) is one of the most demanding challenges for clinical Geneticists and Researchers. Despite molecular diagnostics improvements, the vast majority of patients still remain without genetic diagnosis. Here, we report the results obtained using Whole Exome and Target Sequencing on nine patients affected by isolated ID without pathological copy number variations, which were accurately selected from an initial cohort of 236 patients. Three patterns of inheritance were used to search for: (1) de novo, (2) X-linked, and (3) autosomal recessive variants. In three of the nine proband-parent trios analyzed, we identified and validated two de novo and one X-linked potentially causative mutations located in three ID-related genes. We proposed three genes as ID candidate, carrying one de novo and three X-linked mutations. Overall, this systematic proband-parent trio approach using next generation sequencing could explain a consistent percentage of patients with isolated ID, thus increasing our knowledge on the molecular bases of this disease and opening new perspectives for a better diagnosis, counseling, and treatment.

%B Am J Med Genet A %V 164A %P 170-6 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24307393?dopt=Abstract %R 10.1002/ajmg.a.36274 %0 Journal Article %J Gene %D 2014 %T A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta. %A Rubinato, Elisa %A Morgan, Anna %A D'Eustacchio, Angela %A Pecile, Vanna %A Gortani, Giulia %A Gasparini, Paolo %A Faletra, Flavio %K Child %K Chromosomes, Human, Pair 19 %K DNA Mutational Analysis %K Exons %K Female %K Genes, Recessive %K Homozygote %K Humans %K Ion Channels %K Osteogenesis Imperfecta %K Sequence Deletion %X

Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene.

%B Gene %V 545 %P 290-2 %8 2014 Jul 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24835313?dopt=Abstract %R 10.1016/j.gene.2014.05.028 %0 Journal Article %J Gene %D 2014 %T A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss. %A Faletra, Flavio %A Girotto, Giorgia %A d'Adamo, Adamo Pio %A Vozzi, Diego %A Morgan, Anna %A Gasparini, Paolo %K Amino Acid Sequence %K Deafness %K European Continental Ancestry Group %K Female %K Genotype %K Hearing Loss, Sensorineural %K Humans %K Italy %K Male %K Molecular Sequence Data %K Mutation, Missense %K Pedigree %K Receptors, Purinergic P2X2 %X

Hereditary hearing loss (HHL) is a common disorder accounting for at least 60% of prelingual deafness. It is characterized by a large genetic heterogeneity, and despite the presence of a major gene, still there is a need to search for new causative mutations/genes. Very recently, a mutation within ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) gene (P2RX2) at DNFA41 locus has been reported leading to a bilateral and symmetrical sensorineural non-syndromic autosomal dominant HHL in two Chinese families. We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus. Molecular analyses of P2RX2 identified a novel missense mutation (p.Gly353Arg) affecting a residue highly conserved across species. Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the 'neck' of the region responsible for ion channel gating should have a high energetic cost and should lead to a severely destabilization of the fold. The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL.

%B Gene %V 534 %P 236-9 %8 2014 Jan 25 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24211385?dopt=Abstract %R 10.1016/j.gene.2013.10.052 %0 Journal Article %J Ophthalmic Genet %D 2013 %T A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family. %A Faletra, Flavio %A d'Adamo, Adamo Pio %A Pensiero, Stefano %A Athanasakis, Emmanouil %A Catalano, Dario %A Bruno, Irene %A Gasparini, Paolo %K Amino Acid Sequence %K beta-Crystallin B Chain %K Cataract %K DNA Mutational Analysis %K Female %K Genes, Dominant %K Genetic Linkage %K Genotype %K Humans %K Italy %K Male %K Molecular Sequence Data %K Mutation, Missense %K Pedigree %K Phenotype %X

Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC.

%B Ophthalmic Genet %V 34 %P 115-7 %8 2013 Mar-Jun %G eng %N 1-2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22846113?dopt=Abstract %R 10.3109/13816810.2012.707273 %0 Journal Article %J Gene %D 2012 %T Contribution of SNP arrays in diagnosis of deletion 2p11.2-p12. %A Rocca, Maria Santa %A Fabretto, Antonella %A Faletra, Flavio %A Carlet, Ombretta %A Skabar, Aldo %A Gasparini, Paolo %A Pecile, Vanna %K Abnormalities, Multiple %K Child %K Chromosomes, Human, Pair 2 %K Female %K Humans %K Intellectual Disability %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Sequence Deletion %X

Deletions of the short arm of chromosome 2 are exceedingly rare, having been reported in few patients. Furthermore most cases with deletion in 2p11.2-p12 have been studied using standard karyotype and so it is not possible to delineate the precise size of deletions. Here, we describe a 9-year-old girl with a 9.4 Mb de novo interstitial deletion of region 2p11.2-p12 identified by SNP array analysis. The deleted region encompasses over 40 known genes, including LRRTM1, CTNNA2 and REEP1, haploinsufficiency of which could explain some clinical features of this patient such as mental retardation, speech delay and gait abnormalities. A comparison of our case with previously reported patients who present deletions in 2p11.2-p12 was carried out. Our case adds new information to the deletion of 2p11.2-p12, improving the knowledge on this rearrangement.

%B Gene %V 492 %P 315-8 %8 2012 Jan 15 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22062632?dopt=Abstract %R 10.1016/j.gene.2011.10.035 %0 Journal Article %J J Pediatr Gastroenterol Nutr %D 2012 %T Delayed diagnosis of glycogen storage disease type III. %A Minen, Federico %A Cont, Gabriele %A De Cunto, Angela %A Martelossi, Stefano %A Ventura, Alessandro %A Maggiore, Giuseppe %A Faletra, Flavio %A Gasparini, Paolo %A Cassandrini, Denise %K Delayed Diagnosis %K Diagnostic Errors %K Glycogen Storage Disease Type I %K Glycogen Storage Disease Type III %K Humans %K Infant %K Liver %K Male %B J Pediatr Gastroenterol Nutr %V 54 %P 122-4 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21691223?dopt=Abstract %R 10.1097/MPG.0b013e318228d806 %0 Journal Article %J Am J Med Genet A %D 2012 %T Does the 1.5 Mb microduplication in chromosome band Xp22.31 have a pathogenetic role? New contribution and a review of the literature. %A Faletra, Flavio %A d'Adamo, Adamo Pio %A Santa Rocca, Maria %A Carrozzi, Marco %A Perrone, Maria Dolores %A Pecile, Vanna %A Gasparini, Paolo %K Chromosome Breakpoints %K Chromosome Duplication %K Chromosomes, Human, X %K Hand Deformities, Congenital %K Humans %K Intellectual Disability %K Karyotyping %K Muscle Hypotonia %K Polymorphism, Single Nucleotide %K Protein Tyrosine Phosphatases %B Am J Med Genet A %V 158A %P 461-4 %8 2012 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/22140086?dopt=Abstract %R 10.1002/ajmg.a.34398 %0 Journal Article %J PLoS Genet %D 2012 %T Evidence of inbreeding depression on human height. %A McQuillan, Ruth %A Eklund, Niina %A Pirastu, Nicola %A Kuningas, Maris %A McEvoy, Brian P %A Esko, Tõnu %A Corre, Tanguy %A Davies, Gail %A Kaakinen, Marika %A Lyytikäinen, Leo-Pekka %A Kristiansson, Kati %A Havulinna, Aki S %A Gögele, Martin %A Vitart, Veronique %A Tenesa, Albert %A Aulchenko, Yurii %A Hayward, Caroline %A Johansson, Åsa %A Boban, Mladen %A Ulivi, Sheila %A Robino, Antonietta %A Boraska, Vesna %A Igl, Wilmar %A Wild, Sarah H %A Zgaga, Lina %A Amin, Najaf %A Theodoratou, Evropi %A Polasek, Ozren %A Girotto, Giorgia %A Lopez, Lorna M %A Sala, Cinzia %A Lahti, Jari %A Laatikainen, Tiina %A Prokopenko, Inga %A Kals, Mart %A Viikari, Jorma %A Yang, Jian %A Pouta, Anneli %A Estrada, Karol %A Hofman, Albert %A Freimer, Nelson %A Martin, Nicholas G %A Kähönen, Mika %A Milani, Lili %A Heliövaara, Markku %A Vartiainen, Erkki %A Räikkönen, Katri %A Masciullo, Corrado %A Starr, John M %A Hicks, Andrew A %A Esposito, Laura %A Kolcic, Ivana %A Farrington, Susan M %A Oostra, Ben %A Zemunik, Tatijana %A Campbell, Harry %A Kirin, Mirna %A Pehlic, Marina %A Faletra, Flavio %A Porteous, David %A Pistis, Giorgio %A Widen, Elisabeth %A Salomaa, Veikko %A Koskinen, Seppo %A Fischer, Krista %A Lehtimäki, Terho %A Heath, Andrew %A McCarthy, Mark I %A Rivadeneira, Fernando %A Montgomery, Grant W %A Tiemeier, Henning %A Hartikainen, Anna-Liisa %A Madden, Pamela A F %A d'Adamo, Pio %A Hastie, Nicholas D %A Gyllensten, Ulf %A Wright, Alan F %A van Duijn, Cornelia M %A Dunlop, Malcolm %A Rudan, Igor %A Gasparini, Paolo %A Pramstaller, Peter P %A Deary, Ian J %A Toniolo, Daniela %A Eriksson, Johan G %A Jula, Antti %A Raitakari, Olli T %A Metspalu, Andres %A Perola, Markus %A Järvelin, Marjo-Riitta %A Uitterlinden, André %A Visscher, Peter M %A Wilson, James F %K Adult %K Aged %K Body Height %K Consanguinity %K Databases, Genetic %K Family %K Female %K Genes, Recessive %K Genetic Heterogeneity %K Genome-Wide Association Study %K Homozygote %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Quantitative Trait, Heritable %X

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

%B PLoS Genet %V 8 %P e1002655 %8 2012 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22829771?dopt=Abstract %R 10.1371/journal.pgen.1002655 %0 Journal Article %J Acta Paediatr %D 2012 %T A red baby should not be taken too lightly. %A Faletra, Flavio %A Bruno, Irene %A Berti, Irene %A Pastore, Serena %A Pirrone, Angela %A Tommasini, Alberto %K Child, Preschool %K Dermatitis %K Ectodermal Dysplasia %K Female %K Humans %K Immunologic Deficiency Syndromes %K Infant %K Male %K Netherton Syndrome %K Severe Combined Immunodeficiency %K Skin %X

AIM: To identify clinical and laboratory features that can drive the differential diagnosis of a primary immunodeficiency diseases in patients with ectodermal defects.

METHODS: Analysis of selected teaching cases.

RESULTS: We identified four exemplary cases that allowed to point out specific clues.

CONCLUSIONS: A careful evaluation of immune and ectodermal signs is the key to the diagnosis. Therefore, a multidisciplinary approach can lead to diagnosis and to an appropriate treatment in most of the cases.

%B Acta Paediatr %V 101 %P e573-7 %8 2012 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/22946961?dopt=Abstract %R 10.1111/apa.12018 %0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. %A Wain, Louise V %A Verwoert, Germaine C %A O'Reilly, Paul F %A Shi, Gang %A Johnson, Toby %A Johnson, Andrew D %A Bochud, Murielle %A Rice, Kenneth M %A Henneman, Peter %A Smith, Albert V %A Ehret, Georg B %A Amin, Najaf %A Larson, Martin G %A Mooser, Vincent %A Hadley, David %A Dörr, Marcus %A Bis, Joshua C %A Aspelund, Thor %A Esko, Tõnu %A Janssens, A Cecile J W %A Zhao, Jing Hua %A Heath, Simon %A Laan, Maris %A Fu, Jingyuan %A Pistis, Giorgio %A Luan, Jian'an %A Arora, Pankaj %A Lucas, Gavin %A Pirastu, Nicola %A Pichler, Irene %A Jackson, Anne U %A Webster, Rebecca J %A Zhang, Feng %A Peden, John F %A Schmidt, Helena %A Tanaka, Toshiko %A Campbell, Harry %A Igl, Wilmar %A Milaneschi, Yuri %A Hottenga, Jouke-Jan %A Vitart, Veronique %A Chasman, Daniel I %A Trompet, Stella %A Bragg-Gresham, Jennifer L %A Alizadeh, Behrooz Z %A Chambers, John C %A Guo, Xiuqing %A Lehtimäki, Terho %A Kuhnel, Brigitte %A Lopez, Lorna M %A Polasek, Ozren %A Boban, Mladen %A Nelson, Christopher P %A Morrison, Alanna C %A Pihur, Vasyl %A Ganesh, Santhi K %A Hofman, Albert %A Kundu, Suman %A Mattace-Raso, Francesco U S %A Rivadeneira, Fernando %A Sijbrands, Eric J G %A Uitterlinden, André G %A Hwang, Shih-Jen %A Vasan, Ramachandran S %A Wang, Thomas J %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gerard %A Laitinen, Jaana %A Pouta, Anneli %A Zitting, Paavo %A McArdle, Wendy L %A Kroemer, Heyo K %A Völker, Uwe %A Völzke, Henry %A Glazer, Nicole L %A Taylor, Kent D %A Harris, Tamara B %A Alavere, Helene %A Haller, Toomas %A Keis, Aime %A Tammesoo, Mari-Liis %A Aulchenko, Yurii %A Barroso, Inês %A Khaw, Kay-Tee %A Galan, Pilar %A Hercberg, Serge %A Lathrop, Mark %A Eyheramendy, Susana %A Org, Elin %A Sõber, Siim %A Lu, Xiaowen %A Nolte, Ilja M %A Penninx, Brenda W %A Corre, Tanguy %A Masciullo, Corrado %A Sala, Cinzia %A Groop, Leif %A Voight, Benjamin F %A Melander, Olle %A O'Donnell, Christopher J %A Salomaa, Veikko %A d'Adamo, Adamo Pio %A Fabretto, Antonella %A Faletra, Flavio %A Ulivi, Sheila %A Del Greco, Fabiola M %A Facheris, Maurizio %A Collins, Francis S %A Bergman, Richard N %A Beilby, John P %A Hung, Joseph %A Musk, A William %A Mangino, Massimo %A Shin, So-Youn %A Soranzo, Nicole %A Watkins, Hugh %A Goel, Anuj %A Hamsten, Anders %A Gider, Pierre %A Loitfelder, Marisa %A Zeginigg, Marion %A Hernandez, Dena %A Najjar, Samer S %A Navarro, Pau %A Wild, Sarah H %A Corsi, Anna Maria %A Singleton, Andrew %A de Geus, Eco J C %A Willemsen, Gonneke %A Parker, Alex N %A Rose, Lynda M %A Buckley, Brendan %A Stott, David %A Orru, Marco %A Uda, Manuela %A van der Klauw, Melanie M %A Zhang, Weihua %A Li, Xinzhong %A Scott, James %A Chen, Yii-Der Ida %A Burke, Gregory L %A Kähönen, Mika %A Viikari, Jorma %A Döring, Angela %A Meitinger, Thomas %A Davies, Gail %A Starr, John M %A Emilsson, Valur %A Plump, Andrew %A Lindeman, Jan H %A Hoen, Peter A C 't %A König, Inke R %A Felix, Janine F %A Clarke, Robert %A Hopewell, Jemma C %A Ongen, Halit %A Breteler, Monique %A Debette, Stéphanie %A Destefano, Anita L %A Fornage, Myriam %A Mitchell, Gary F %A Smith, Nicholas L %A Holm, Hilma %A Stefansson, Kari %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Samani, Nilesh J %A Preuss, Michael %A Rudan, Igor %A Hayward, Caroline %A Deary, Ian J %A Wichmann, H-Erich %A Raitakari, Olli T %A Palmas, Walter %A Kooner, Jaspal S %A Stolk, Ronald P %A Jukema, J Wouter %A Wright, Alan F %A Boomsma, Dorret I %A Bandinelli, Stefania %A Gyllensten, Ulf B %A Wilson, James F %A Ferrucci, Luigi %A Schmidt, Reinhold %A Farrall, Martin %A Spector, Tim D %A Palmer, Lyle J %A Tuomilehto, Jaakko %A Pfeufer, Arne %A Gasparini, Paolo %A Siscovick, David %A Altshuler, David %A Loos, Ruth J F %A Toniolo, Daniela %A Snieder, Harold %A Gieger, Christian %A Meneton, Pierre %A Wareham, Nicholas J %A Oostra, Ben A %A Metspalu, Andres %A Launer, Lenore %A Rettig, Rainer %A Strachan, David P %A Beckmann, Jacques S %A Witteman, Jacqueline C M %A Erdmann, Jeanette %A van Dijk, Ko Willems %A Boerwinkle, Eric %A Boehnke, Michael %A Ridker, Paul M %A Järvelin, Marjo-Riitta %A Chakravarti, Aravinda %A Abecasis, Goncalo R %A Gudnason, Vilmundur %A Newton-Cheh, Christopher %A Levy, Daniel %A Munroe, Patricia B %A Psaty, Bruce M %A Caulfield, Mark J %A Rao, Dabeeru C %A Tobin, Martin D %A Elliott, Paul %A van Duijn, Cornelia M %K Arteries %K Blood Pressure %K Case-Control Studies %K Follow-Up Studies %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Linkage Disequilibrium %K Polymorphism, Single Nucleotide %X

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

%B Nat Genet %V 43 %P 1005-11 %8 2011 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract %R 10.1038/ng.922 %0 Journal Article %J Ophthalmic Genet %D 2011 %T Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations. %A Abu-Amero, Khaled K %A Faletra, Flavio %A Gasparini, Paolo %A Parentin, Fulvio %A Pensiero, Stefano %A Alorainy, Ibrahim A %A Hellani, Ali M %A Catalano, Dario %A Bosley, Thomas M %K Child %K Humans %K Kyphosis %K Magnetic Resonance Imaging %K Male %K Mutation %K Ocular Motility Disorders %K Oculomotor Nerve Diseases %K Pedigree %K Receptors, Immunologic %K Scoliosis %X

BACKGROUND: To describe clinical and genetic observations in a patient with horizontal gaze palsy and progressive scoliosis (HGPPS) without identified mutations in the ROBO3 gene.

MATERIALS AND METHODS: Neurologic and orthopedic evaluation of the proband; sequencing all exons, exon-intron boundaries, and promoter region of ROBO3 in the proband and his mother. Array CGH was also carried out in the proband and his mother to evaluate possible chromosomal deletion(s) and/or duplication(s).

RESULTS: The proband had complete horizontal gaze restriction with full vertical gaze and small amplitude horizontal pendular nystagmus. He also had severe scoliosis and brainstem hypoplasia pathognomonic of HGPPS. However, complete sequencing of ROBO3 twice in both forward and reverse directions did not reveal any mutations. Array CGH investigation revealed no chromosomal abnormalities.

CONCLUSIONS: This patient had clinical and neuroimaging characteristics considered pathognomonic of HGPPS and yet did not have ROBO3 mutations. A clinical misdiagnosis is unlikely in the absence of facial weakness (typical of Moebius syndrome), deafness (typical of the HOXA1 spectrum), or mental retardation (typical of other central decussation abnormalities). It is perhaps more likely that a phenotype identical to HGPPS can be caused by abnormalities in ROBO3 splice variant expression, by mutations of a gene other than ROBO3, or by some environmental or epigenetic factor(s) inhibiting the action of ROBO3 or its protein product in the developing brainstem.

%B Ophthalmic Genet %V 32 %P 212-6 %8 2011 Nov %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21510772?dopt=Abstract %R 10.3109/13816810.2011.574186 %0 Journal Article %J J Appl Genet %D 2011 %T A new case of duplication of the MDS region identified by high-density SNP arrays and a review of the literature. %A Faletra, Flavio %A Devescovi, Raffaella %A Pecile, Vanna %A Fabretto, Antonella %A Carrozzi, Marco %A Gasparini, Paolo %K 1-Alkyl-2-acetylglycerophosphocholine Esterase %K Child %K Female %K Gene Duplication %K Humans %K Microtubule-Associated Proteins %K Myelodysplastic Syndromes %K Oligonucleotide Array Sequence Analysis %K Polymorphism, Single Nucleotide %K Prognosis %B J Appl Genet %V 52 %P 77-80 %8 2011 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21107783?dopt=Abstract %R 10.1007/s13353-010-0004-2 %0 Journal Article %J Ophthalmic Genet %D 2011 %T Vertebral defects in patients with Peters plus syndrome and mutations in B3GALTL. %A Faletra, Flavio %A Athanasakis, Emmanouil %A Minen, Federico %A Fornasier, Federico %A Marchetti, Federico %A Gasparini, Paolo %K Abnormalities, Multiple %K Alternative Splicing %K Child, Preschool %K Cleft Lip %K Consanguinity %K Cornea %K Female %K Galactosyltransferases %K Glucosyltransferases %K Growth Disorders %K Humans %K Limb Deformities, Congenital %K Point Mutation %K Spine %B Ophthalmic Genet %V 32 %P 256-8 %8 2011 Nov %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21671750?dopt=Abstract %R 10.3109/13816810.2011.587082 %0 Journal Article %J Ophthalmic Genet %D 2010 %T A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation. %A Fabretto, Antonella %A Shardlow, Alison %A Faletra, Flavio %A Lepore, Loredana %A Hladnik, Uros %A Gasparini, Paolo %K Abnormalities, Multiple %K Adolescent %K Eye Abnormalities %K Eyelashes %K Face %K Forkhead Transcription Factors %K Frameshift Mutation %K Humans %K Lymphedema %K Male %K Syndrome %X

PURPOSE: Lymphedema-Distichiasis (LD, OMIM 153400) is an autosomal dominant disorder with variable expression. The mutated gene implicated is FOXC2, which encodes for a forkhead transcription factor involved in the development of the lymphatic and vascular system. LD is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis. Other associations have been reported, including congenital heart disease, ptosis, scoliosis.

CONCLUSIONS: Here we describe a case of LD carrying a de novo frameshift mutation of FOXC2 who presented a prepubertal onset of lower limbs lymphedema and mild distichiasis associated with other anomalies such as webbing neck and ptosis.

%B Ophthalmic Genet %V 31 %P 98-100 %8 2010 Jun %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20450314?dopt=Abstract %R 10.3109/13816811003620517