Publications by authors named "Enrico Grosso"

43 Publications

Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I.

Genes Chromosomes Cancer 2021 Aug 24. Epub 2021 Aug 24.

Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy.

Neurofibromatosis type I, a genetic condition due to pathogenic variants in the NF1 gene, is burdened by a high rate of complications, including neoplasms, which increase morbidity and mortality for the disease. We retrospectively re-evaluated the NF1 gene variants found in the period 2000-2019 and we studied for genotype/phenotype correlations of disease complications and neoplasms 34 variants, which were shared by at least two unrelated families (range 2-11) for a total 141 of probands and 21 relatives affected by Neurofibromatosis type I. Recurrent variants could be ascribed to the most common mutational mechanisms (C to T transition, microsatellite slippage, non-homologous recombination). In genotype/phenotype correlations, the variants p.Arg440*, p.Tyr489Cys, and p.Arg1947*, together with the gross gene deletions, displayed the highest rates of complications. When considering neoplasms, carriers of variants falling in the extradomain region at the 5' end of NF1 had a lower age-related cancer frequency than the rest of the gene sequence, showing a borderline significance (p = 0.045), which was not conserved after correction with covariates. We conclude that (1) hotspots in NF1 occur via different mutational mechanisms, (2) several variants are associated with high rates of complications and cancers, and (3) there is an initial evidence toward a lower cancer risk for carriers of variants in the 5' end of the NF1 gene although not significant at the multivariate analysis.
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http://dx.doi.org/10.1002/gcc.22997DOI Listing
August 2021

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

Genes (Basel) 2021 04 27;12(5). Epub 2021 Apr 27.

Istituto Auxologico Italiano, IRCCS, Laboratory of Medical Cytogenetics and Molecular Genetics, 20145 Milan, Italy.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which , , , and are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only , and genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of and better define how the two contiguous genes, and , might contribute to the clinical phenotype.
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http://dx.doi.org/10.3390/genes12050652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146486PMC
April 2021

Diagnosis of maternal Hodgkin lymphoma following abnormal findings at noninvasive prenatal screening test (NIPT): Report of two cases.

Clin Case Rep 2021 Mar 13;9(3):1066-1071. Epub 2021 Jan 13.

AO Santa Croce e Carle di Cuneo Cuneo Italy.

Abnormal NIPT results, contrasting with normal fetus development, could disclose maternal malignancy, and this possibility should always be explained during pretest counseling. In this case, a complete diagnostic assessment is recommended and should be managed by a multidisciplinary team to define the best timing for diagnostic procedures, delivery, and treatment.
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http://dx.doi.org/10.1002/ccr3.3593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981684PMC
March 2021

Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review.

Am J Med Genet A 2021 06 6;185(6):1712-1720. Epub 2021 Mar 6.

Department of Medical Sciences, University of Turin, Turin, Italy.

De novo variants in the WDR26 gene leading to haploinsufficiency have recently been associated with Skraban-Deardorff syndrome. This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs, including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies. Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available. Here, we describe a child with Skraban-Deardorff syndrome associated with the WDR26 pathogenic de novo variant NM_025160.6:c.69dupC, p.(Gly24ArgfsTer48), and an adult associated with the pathogenic de novo variant c.1076G > A, p.(Trp359Ter). The adult patient was a 29-year-old female with detailed information on clinical history and pharmacological treatments since birth, providing an opportunity to map disease progression and patient management. By comparing our cases with published reports of Skraban-Deardorff syndrome, we provide a genetic and clinical summary of this ultrarare condition, describe the clinical management from childhood to adult age, and further expand on the clinical phenotype.
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http://dx.doi.org/10.1002/ajmg.a.62157DOI Listing
June 2021

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort.

Genet Med 2021 06 10;23(6):1116-1124. Epub 2021 Feb 10.

Pediatrics Department, Medical Genetics Division, CHU Sainte-Justine, Montreal, QC, Canada.

Purpose: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype-phenotype correlations.

Methods: Three hundred fifty-two chromosomal microarray-negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons.

Results: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM.

Conclusion: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.
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http://dx.doi.org/10.1038/s41436-020-01093-7DOI Listing
June 2021

Correction to: Malignant struma ovarii: next-generation sequencing of six cases revealed Nras, Braf, and Jak3 mutations.

Endocrine 2020 Dec;70(3):661

Pathology Unit, Department of Oncology, University of Turin, via Santena 7, 10126, Turin, Italy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1007/s12020-020-02514-yDOI Listing
December 2020

Biallelic mutations in the gene cause a novel primary ciliopathy.

J Med Genet 2021 Aug 3;58(8):526-533. Epub 2020 Aug 3.

Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Padova, Italy

Background: Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.

Objective: To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.

Methods: A trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the gene. In silico, in vitro and in vivo () studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes.

Results: encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in , , is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding.

Conclusions: Our data are in favour of a causative role of variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy.
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http://dx.doi.org/10.1136/jmedgenet-2020-106833DOI Listing
August 2021

Malignant struma ovarii: next-generation sequencing of six cases revealed Nras, Braf, and Jak3 mutations.

Endocrine 2021 01 2;71(1):216-224. Epub 2020 Aug 2.

Pathology Unit, Department of Oncology, University of Turin, via Santena 7, 10126, Turin, Italy.

Purpose: Struma ovarii (SO) is a highly specialized ovarian teratoma, consisting of thyroid tissue. Rarely, carcinomas histologically identical to their thyroid counterparts may occur, and are comprehensively defined as malignant struma ovarii (MSO). Their optimal management is controversial, and the molecular profile of the malignant counterpart in the ovary is incompletely known. In this study, the clinicopathological and molecular features of six MSO from different Italian Institutions were analysed, to explore genetic profiles of potential therapeutic interest.

Methods: The histopathological features and immunoprofile (according to the known markers Galectin-3, HBME1, cytokeratin 19 and CD56) were reviewed. In addition, all cases underwent genetic analysis with a next-generation sequencing (NGS) hot spot cancer panel detecting mutations in 50 genes involved in cancerogenesis. RET/PTC rearrangements and TERT promoter alterations were also evaluated.

Results: Papillary carcinoma in all similar to its thyroid counterpart was found in five of six cases, including classical (two tumors) and follicular variant (three tumors) types. The last case was a poorly differentiated carcinoma. An activating gene mutation, was detected in five of six cases, including two NRAS, two BRAF, and one JAK3 oncogene mutations. No alterations were found in the other panel genes, nor in TERT promoter, or in RET chromosomal regions.

Conclusions: MSO is a rare condition. Papillary carcinoma is the predominant malignant type, sharing both histomorphological and molecular features of its thyroid counterpart. Interestingly, the single case of poorly differentiated carcinoma displayed a JAK3 mutation. The presence of such driving mutation could be of potential interest in guiding postoperative treatment.
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http://dx.doi.org/10.1007/s12020-020-02438-7DOI Listing
January 2021

Molecular characterisation and clinical correlation of papillary thyroid microcarcinoma.

Endocrine 2021 01 3;71(1):149-157. Epub 2020 Jul 3.

Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Città della Salute e della Scienza, Torino, Italy.

Purpose: Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis, a subset of mPTCs shows potentially aggressive behaviour.

Methods: To search for predictors of clinical outcome of mPTCs, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF, NRAS and TERT promoter mutations as well as RET/PTC translocations.

Results: Mean follow-up period was 8.4 ± 3.6 years. In 55 cases, mPTC were detected incidentally after surgery. Capsular invasion, bilateralism and multifocality were found in 11/100, 17/100 and 24/100 cases, respectively, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed, three in laterocervical lymph-nodes), while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAF was the most frequently detected (49/100) and was associated with higher tumour size, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases, NRAS in 4/100, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAF mutation and unfavourable histopathological features, we found no direct association with tumour recurrence, distant metastases and mortality.

Conclusion: In our study, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.
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http://dx.doi.org/10.1007/s12020-020-02380-8DOI Listing
January 2021

Gene Panel Analysis in a Large Cohort of Patients With Autosomal Dominant Polycystic Kidney Disease Allows the Identification of 80 Potentially Causative Novel Variants and the Characterization of a Complex Genetic Architecture in a Subset of Families.

Front Genet 2020 7;11:464. Epub 2020 May 7.

Nephrology, Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. Orsola-Malpighi University Hospital, Bologna, Italy.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans and the majority of patients carry a variant in either or . Genetic testing is increasingly required for diagnosis, prognosis, and treatment decision, but it is challenging due to segmental duplications of , genetic and allelic heterogeneity, and the presence of many variants hypomorphic or of uncertain significance. We propose an NGS-based testing strategy for molecular analysis of ADPKD and its phenocopies, validated in a diagnostic setting. Our protocol is based on high-throughput simultaneous sequencing of and after long range PCR of coding regions, followed by a masked reference genome alignment, and MLPA analysis. A further screening of additional 14 cystogenes was performed in negative cases. We applied this strategy to analyze 212 patients with a clinical suspicion of ADPKD. We detected causative variants (interpreted as pathogenic/likely pathogenic) in 61.3% of our index patients, and variants of uncertain clinical significance in 12.5%. The majority (88%) of genetic variants was identified in , 12% in . Among 158 distinct variants, 80 (50.6%) were previously unreported, confirming broad allelic heterogeneity. Eleven patients showed more than one variant. Segregation analysis indicated biallelic disease in five patients, digenic in one, variant with unknown phase in two. Furthermore, our NGS protocol allowed the identification of two patients with somatic mosaicism, which was undetectable with Sanger sequencing. Among patients without / variants, we identified three with possible alternative diagnosis: a patient with biallelic mutations in , confirming the overlap between recessive and dominant PKD, and two patients with variants in and , respectively. Genotype-phenotype correlations showed that patients with variants predicted to truncate (T) the protein experienced end-stage renal disease 9 years earlier than patients with non-truncating (NT) mutations and >13 years earlier than patients with mutations. ADPKD- cases showed a disease onset significantly earlier than ADPKD- and ADPK-, as well as a significant earlier diagnosis. These data emphasize the need to combine clinical information with genetic data to achieve useful prognostic predictions.
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http://dx.doi.org/10.3389/fgene.2020.00464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224062PMC
May 2020

The largest caucasian kindred with dentatorubral-pallidoluysian atrophy: A founder mutation in italy.

Mov Disord 2019 12 21;34(12):1919-1924. Epub 2019 Nov 21.

Regional Neurogenetic Center (CRN), ASP Catanzaro, Lamezia Terme, Italy.

Background: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features.

Methods: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed.

Results: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset.

Conclusions: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27879DOI Listing
December 2019

Design of a multiplex ligation-dependent probe amplification assay for SLC20A2: identification of two novel deletions in primary familial brain calcification.

J Hum Genet 2019 Nov 9;64(11):1083-1090. Epub 2019 Sep 9.

Department of Medical Sciences, University of Torino, Turin, Italy.

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.
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http://dx.doi.org/10.1038/s10038-019-0668-3DOI Listing
November 2019

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

Nat Commun 2019 07 12;10(1):3094. Epub 2019 Jul 12.

Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 526121, Ramat Gan, Israel.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.
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http://dx.doi.org/10.1038/s41467-019-10910-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626132PMC
July 2019

Congenital Sensorineural Hearing Loss and Inborn Pigmentary Disorders: First Report of Multilocus Syndrome in Piebaldism.

Medicina (Kaunas) 2019 Jul 7;55(7). Epub 2019 Jul 7.

Department of Health Sciences, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.

Congenital sensorineural hearing loss may occur in association with inborn pigmentary defects of the iris, hair, and skin. These conditions, named auditory-pigmentary disorders (APDs), represent extremely heterogeneous hereditary diseases, including Waardenburg syndromes, oculocutaneous albinism, Tietz syndrome, and piebaldism. APDs are part of the neurocristopathies, a group of congenital multisystem disorders caused by an altered development of the neural crest cells, multipotent progenitors of a wide variety of different lineages, including those differentiating into peripheral nervous system glial cells and melanocytes. We report on clinical and genetic findings of two monozygotic twins from a large Albanian family who showed a complex phenotype featured by sensorineural congenital deafness, severe neuropsychiatric impairment, and inborn pigmentary defects of hair and skin. The genetic analyzes identified, in both probands, an unreported co-occurrence of a new heterozygous germline pathogenic variant (c.2484 + 5G > T splicing mutation) in the gene, consistent with the diagnosis of piebaldism, and a heterozygous deletion at chromosome 15q13.3, responsible for the neuropsychiatric impairment. This case represents the first worldwide report of dual locus inherited syndrome in piebald patients affected by a complex auditory-pigmentary multisystem phenotype. Here we also synthesize the clinical and genetic findings of all known neurocristopathies characterized by a hypopigmentary congenital disorder.
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http://dx.doi.org/10.3390/medicina55070345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681376PMC
July 2019

On the Complexity of Visual Judgement of Kinship.

Iperception 2019 May-Jun;10(3):2041669519841642. Epub 2019 May 6.

University of Sassari, Italy.

Discrimination of close relatives is a basic ability of humans, with demonstrated and important consequences in social and sexual behaviours. In this article, we investigate the visual judgement of kinship, that is the process of discriminating relatives based on visual cues and, in particular, on facial resemblance. Starting from triplets of face stimuli, we focus on a simple two-alternative forced choice protocol and we ask participants to evaluate kinship, similarity, or dissimilarity. Response times of the participants performing these visual judgements are recorded and further analysed. The analysis can also benefit from previous findings on the adopted face data set; in particular, results are compared with reference to an independently generated and statistically reliable similarity index, which is available for each possible considered pair of images. Our results confirm previous findings stating that kinship and similarity judgements are closely related and take longer, on average, than dissimilarity judgement. Moreover, they confirm that similarity and dissimilarity cannot be considered just as opposite concepts, and strongly support the existence of different pathways for similarity and dissimilarity judgements. Concerning kinship judgements, results confirm the assumption, inherent in previous models, of a close relationship between cues signalling for kinship and cues signalling for similarity but suggest the existence of a more complex process, where dissimilarity cues need to be explicitly included in order to model measured effects. Our results reinforce the idea that modulation mechanisms between similarity and dissimilarity measures could explain selective suppression or enhancement effects reported in previous works. A new framework is thus proposed hypothesising that kinship recognition is the result of a balanced evaluation of both similar or dissimilar pathways.
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http://dx.doi.org/10.1177/2041669519841642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505255PMC
May 2019

Assessment of a High Sensitivity Method for Identification of R132x Mutations in Tumors and Plasma of Intrahepatic Cholangiocarcinoma Patients.

Cancers (Basel) 2019 Mar 30;11(4). Epub 2019 Mar 30.

Department of Oncology, University of Turin, 10100 Torino, Italy.

Hotspot codon 132 mutations (R132xm) are frequent in intrahepatic cholangiocarcinoma (ICC), are druggable by anti-m agents, and could represent a marker of disease progression. Developing an assay to identify R132xm would provide a useful tool to select patients benefitting from targeted treatments. We tested a quantitative real-time allele-specific polymerase chain reaction (qPCR)-based method to detect the main R132xm in an Italian ICC series ( = 61) of formalin-fixed paraffin-embedded (FFPE) samples, and on circulating-free DNA samples. The outcomes were compared with nested PCR/Sanger sequencing. Reconstitution experiments of plasmids harboring the different R132xm mixed with wild-type (WT) DNA demonstrated that qPCR is able to detect at least 2% of all mutated allele. High efficiency was also observed on patient-derived mutated DNA mixed with WT DNA (up to 10% and 0.3 ng of mutated template); qPCR detected 16.4% of mutated samples (one R132G, three R132C and six R132L) while nested PCR/Sanger sequencing only 8.2% (four R132L and one R132G). In a single patient with an R132C-mutated tumor, qPCR was also performed on plasma samples collected at four time-points, observing an increase correlating with disease progression. In conclusion, we developed a qPCR assay which could represent a fast, inexpensive and sensitive tool both for detection of R132xm in ICC samples and monitoring disease progression from liquid biopsy.
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http://dx.doi.org/10.3390/cancers11040454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521091PMC
March 2019

Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations.

Front Genet 2018 21;9:681. Epub 2018 Dec 21.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Hereditary hearing loss (HHL) is a common disorder characterized by a huge genetic heterogeneity. The definition of a correct molecular diagnosis is essential for proper genetic counseling, recurrence risk estimation, and therapeutic options. From 20 to 40% of patients carry mutations in gene, thus, in more than half of cases it is necessary to look for causative variants in the other genes so far identified (~100). In this light, the use of next-generation sequencing technologies has proved to be the best solution for mutational screening, even though it is not always conclusive. Here we describe a combined approach, based on targeted re-sequencing (TRS) of 96 HHL genes followed by high-density SNP arrays, aimed at the identification of the molecular causes of non-syndromic HHL (NSHL). This strategy has been applied to study 103 Italian unrelated cases, negative for mutations in , and led to the characterization of 31% of them (i.e., 37% of familial and 26.3% of sporadic cases). In particular, TRS revealed and genes as major players in the Italian population. Furthermore, two missense variants in 1 have been identified and investigated through protein modeling and molecular dynamics simulations, confirming their likely pathogenic effect. Among the selected patients analyzed by SNP arrays (negative to TRS, or with a single variant in a recessive gene) a molecular diagnosis was reached in ~36% of cases, highlighting the importance to look for large insertions/deletions. Moreover, copy number variants analysis led to the identification of the first case of uniparental disomy involving gene. Overall, taking into account the contribution of , plus the results from TRS and SNP arrays, it was possible to reach a molecular diagnosis in ~51% of NSHL cases. These data proved the usefulness of a combined approach for the analysis of NSHL and for the definition of the epidemiological picture of HHL in the Italian population.
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http://dx.doi.org/10.3389/fgene.2018.00681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309105PMC
December 2018

A novel case of Greenberg dysplasia and genotype-phenotype correlation analysis for LBR pathogenic variants: An instructive example of one gene-multiple phenotypes.

Am J Med Genet A 2019 02 18;179(2):306-311. Epub 2018 Dec 18.

Department of Medical Sciences, University of Torino, Torino, Italy.

Greenberg skeletal dysplasia is an autosomal recessive, perinatal lethal disorder associated with biallelic variants affecting the lamin B receptor (LBR) gene. LBR is also associated with the autosomal recessive anadysplasia-like spondylometaphyseal dysplasia, and the autosomal dominant Pelger-Huët anomaly, a benign laminopathy characterized by anomalies in the nuclear shape of blood granulocytes. The LBR is an inner nuclear membrane protein that binds lamin B proteins (LMNB1 and LMNB2), interacts with chromatin, and exerts a sterol reductase activity. Here, we report on a novel LBR missense variant [c.1379A>G; p.(D460R)], identified by whole exome sequencing and causing Greenberg dysplasia in two fetuses from a consanguineous Moroccan family. We revised published LBR variants to propose a genotype-phenotype correlation in LBR associated diseases. The diverse phenotypes are correlated to the functional domain affected, the heterozygous or homozygous state of the variants, and their different impact on the residual protein function. LBR represents an instructive example of one gene presenting with two different patterns of inheritance and at least three different clinical phenotypes.
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http://dx.doi.org/10.1002/ajmg.a.61000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349533PMC
February 2019

Three novel missense mutations in SLC20A2 associated with idiopathic basal ganglia calcification.

J Neurol Sci 2017 06 31;377:62-64. Epub 2017 Mar 31.

Koelliker Hospital, 10134 Torino, Italy; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, 10126 Torino, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2017.03.053DOI Listing
June 2017

The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.

Kidney Int 2017 05 21;91(5):1243-1255. Epub 2017 Feb 21.

Medical Genetics, Department of Clinical and Experimental Medicine, University Hospital of Parma, Italy.

Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.
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http://dx.doi.org/10.1016/j.kint.2016.12.017DOI Listing
May 2017

A case of Feingold type 2 syndrome associated with keratoconus refines keratoconus type 7 locus on chromosome 13q.

Eur J Med Genet 2017 Apr 31;60(4):224-227. Epub 2017 Jan 31.

Città Della Salute e Della Scienza University Hospital, Medical Genetics Unit, Turin, 10126 Italy; University of Torino, Department of Medical Sciences, Turin, 10126, Italy. Electronic address:

We report on a 58-year old woman with microcephaly, mild dysmorphic features, bilateral keratoconus, digital abnormalities, short stature and mild cognitive delay. Except for keratoconus, the phenotype was suggestive for Feingold syndrome type 2 (FGLDS2, MIM 614326), a rare autosomal dominant disorder described in six patients worldwide, due to the haploinsufficiency of MIR17HG, a micro RNA encoding gene. Karyotype showed a de novo deletion on chromosome 13q, further defined by array-Comparative Genomic Hybridization (a-CGH) to a 17.2-Mb region. The deletion included MIR17HG, as expected by the FGLDS2 phenotype, and twelve genes from the keratoconus type 7 locus. Because our patient presented with keratoconus, we propose she further refines disease genes at this locus. Among previously suggested candidates, we exclude DOCK9 and STK24, and propose as best candidates IPO5, DNAJC3, MBNL2 and RAP2A. In conclusion, we report a novel phenotypic association of Feingold syndrome type 2 and keratoconus, a likely contiguous gene syndrome due to a large genomic deletion on 13q spanning MIR17HG and a still to be identified gene for keratoconus.
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http://dx.doi.org/10.1016/j.ejmg.2017.01.010DOI Listing
April 2017

Array-Comparative Genomic Hybridization Analysis in Fetuses with Major Congenital Malformations Reveals that 24% of Cases Have Pathogenic Deletions/Duplications.

Cytogenet Genome Res 2015 12;147(1):10-6. Epub 2015 Dec 12.

Department of Medical Sciences, University of Torino, Turin, Italy.

Karyotyping and aCGH are routinely used to identify genetic determinants of major congenital malformations (MCMs) in fetal deaths or terminations of pregnancy after prenatal diagnosis. Pathogenic rearrangements are found with a variable rate of 9-39% for aCGH. We collected 33 fetuses, 9 with a single MCM and 24 with MCMs involving 2-4 organ systems. aCGH revealed copy number variants in 14 out of 33 cases (42%). Eight were classified as pathogenic which account for a detection rate of 24% (8/33) considering fetuses with 1 or more MCMs and 33% (8/24) taking into account fetuses with multiple malformations only. Three of the pathogenic variants were known microdeletion syndromes (22q11.21 deletion, central chromosome 22q11.21 deletion, and TAR syndrome) and 5 were large rearrangements, adding up to >11 Mb per subject and comprising strong phenotype-related genes. One of those was a de novo complex rearrangement, and the remaining 4 duplications and 2 deletions were 130-900 kb in size, containing 1-7 genes, and were classified as variants of unknown clinical significance. Our study confirms aCGH as a powerful technique to ascertain the genetic etiology of fetal major congenital malformations.
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http://dx.doi.org/10.1159/000442308DOI Listing
June 2016

A new case of 13q12.2q13.1 microdeletion syndrome contributes to phenotype delineation.

Case Rep Genet 2014 23;2014:470830. Epub 2014 Nov 23.

Department of Medical Sciences, University of Torino, Via Santena 19, 10126 Torino, Italy ; Medical Genetics, "Città della Salute e della Scienza" University Hospital, 10126 Torino, Italy.

A recently described genetic disorder has been associated with 13q12.3 microdeletion spanning three genes, namely, KATNAL1, LINC00426, and HMGB1. Here, we report a new case with similar clinical features that we have followed from birth to 5 years old. The child carried a complex rearrangement with a double translocation: 46,XX,t(7;13)(p15;q14),t(11;15)(q23;q22). Array-CGH identified a de novo microdeletion at 13q12.2q13.1 spanning 3-3.4 Mb and overlapping 13q12.3 critical region. Clinical features resembling those reported in the literature confirm the existence of a distinct 13q12.3 microdeletion syndrome and provide further evidence that is useful to characterize its phenotypic expression during the 5 years of development.
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http://dx.doi.org/10.1155/2014/470830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259072PMC
December 2014

Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH.

Mol Cytogenet 2014 19;7(1):82. Epub 2014 Nov 19.

Department of Medical Sciences, University of Torino, via Santena 19, 10126 Torino, Italy ; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Turin, Italy.

Background: Conventional karyotyping (550 bands resolution) is able to identify chromosomal aberrations >5-10 Mb, which represent a known cause of intellectual disability/developmental delay (ID/DD) and/or multiple congenital anomalies (MCA). Array-Comparative Genomic Hybridization (array-CGH) has increased the diagnostic yield of 15-20%.

Results: In a cohort of 700 ID/DD cases with or without MCA, including 15 prenatal diagnoses, we identified a subgroup of seven patients with a normal karyotype and a large complex rearrangement detected by array-CGH (at least 6, and up to 18 Mb). FISH analysis could be performed on six cases and showed that rearrangements were translocation derivatives, indistinguishable from a normal karyotype as they involved a similar band pattern and size. Five were inherited from a parent with a balanced translocation, whereas two were apparently de novo. Genes spanning the rearrangements could be associated with some phenotypic features in three cases (case 3: DOCK8; case 4: GATA3, AKR1C4; case 6: AS/PWS deletion, CHRNA7), and in two, likely disease genes were present (case 5: NR2F2, TP63, IGF1R; case 7: CDON). Three of our cases were prenatal diagnoses with an apparently normal karyotype.

Conclusions: Large complex rearrangements of up to 18 Mb, involving chromosomal regions with similar size and band appearance may be overlooked by conventional karyotyping. Array-CGH allows a precise chromosomal diagnosis and recurrence risk definition, further confirming this analysis as a first tier approach to clarify molecular bases of ID/DD and/or MCA. In prenatal tests, array-CGH is confirmed as an important tool to avoid false negative results due to karyotype intrinsic limit of detection.
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http://dx.doi.org/10.1186/s13039-014-0082-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4247713PMC
December 2014

Design and validation of a pericentromeric BAC clone set aimed at improving diagnosis and phenotype prediction of supernumerary marker chromosomes.

Mol Cytogenet 2013 Oct 30;6(1):45. Epub 2013 Oct 30.

Laboratorio di Citogenetica Medica e Genetica Molecolare, IRCCS Istituto Auxologico Italiano, via Ariosto 13, 20145, Milano, Italy.

Background: Small supernumerary marker chromosomes (sSMCs) are additional, structurally abnormal chromosomes, generally smaller than chromosome 20 of the same metaphase spread. Due to their small size, they are difficult to characterize by conventional cytogenetics alone. In regard to their clinical effects, sSMCs are a heterogeneous group: in particular, sSMCs containing pericentromeric euchromatin are likely to be associated with abnormal outcomes, although exceptions have been reported. To improve characterization of the genetic content of sSMCs, several approaches might be applied based on different molecular and molecular-cytogenetic assays, e.g., fluorescent in situ hybridization (FISH), array-based comparative genomic hybridization (array CGH), and multiplex ligation-dependent probe amplification (MLPA).To provide a complementary tool for the characterization of sSMCs, we constructed and validated a new, FISH-based, pericentromeric Bacterial Artificial Chromosome (BAC) clone set that with a high resolution spans the most proximal euchromatic sequences of all human chromosome arms, excluding the acrocentric short arms.

Results: By FISH analysis, we assayed 561 pericentromeric BAC probes and excluded 75 that showed a wrong chromosomal localization. The remaining 486 probes were used to establish 43 BAC-based pericentromeric panels. Each panel consists of a core, which with a high resolution covers the most proximal euchromatic ~0.7 Mb (on average) of each chromosome arm and generally bridges the heterochromatin/euchromatin junction, as well as clones located proximally and distally to the core. The pericentromeric clone set was subsequently validated by the characterization of 19 sSMCs. Using the core probes, we could rapidly distinguish between heterochromatic (1/19) and euchromatic (11/19) sSMCs, and estimate the euchromatic DNA content, which ranged from approximately 0.13 to more than 10 Mb. The characterization was not completed for seven sSMCs due to a lack of information about the covered region in the reference sequence (1/19) or sample insufficiency (6/19).

Conclusions: Our results demonstrate that this pericentromeric clone set is useful as an alternative tool for sSMC characterization, primarily in cases of very small SMCs that contain either heterochromatin exclusively or a tiny amount of euchromatic sequence, and also in cases of low-level or cryptic mosaicism. The resulting data will foster knowledge of human proximal euchromatic regions involved in chromosomal imbalances, thereby improving genotype-phenotype correlations.
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http://dx.doi.org/10.1186/1755-8166-6-45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176193PMC
October 2013

Bilaterally cleft lip and bilateral thumb polydactyly with triphalangeal component in a patient with two de novo deletions of HSA 4q32 and 4q34 involving PDGFC, GRIA2, and FBXO8 genes.

Am J Med Genet A 2013 Oct 16;161A(10):2656-62. Epub 2013 Aug 16.

Department of Medical Sciences, University of Torino, Torino, Italy.

We report on a newborn boy with a bilateral cleft of the primary palate, duplicated triphalangeal thumbs, and a patent foramen ovale. During childhood he had moderate developmental delay. Brain MRI at 4 years was normal. The concurrence of non-syndromic clefts of the lip/palate (CL/P) and duplicated thumbs with triphalangeal component has, to our knowledge, not been reported so far. In our case, array-CGH analysis documented two de novo deletions (∼1.2 Mb and ∼400 Kb) of the long arm of chromosome 4, containing four genes: platelet-derived growth factor C (PDGFC), glycine receptor beta subunit (GLRB), glutamate receptor ionotropic AMPA2 (GRIA2), and F-box protein 8 gene (FBXO8). PDGFC codes for a mesenchymal cell growth factor already known to be associated with clefts of the lip. Pdgfc(-/-) mice have skeletal anomalies, and facial schisis resembling human cleft/lip palate. GRIA2 codes for a ligand-activated cation channel that mediates the fast component of postsynaptic excitatory currents in neurons, and may be linked to cognitive dysfunction. FBXO8, a gene of unknown function, is a member of the F-box gene family, among which FBXW4, within the minimal duplicated region associated with human split-hand/foot malformation type 3 (SHFM type 3). The presence of overlapping deletions in patients who do not share the same phenotype of our case suggests incomplete penetrance, and a possible effect of modifier genetic factors.
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http://dx.doi.org/10.1002/ajmg.a.36146DOI Listing
October 2013

A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia.

J Med Genet 2013 Aug 7;50(8):543-51. Epub 2013 Jun 7.

Department of Medical Sciences, University of Torino, Turin, Italy.

Background And Aim: We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia.

Methods And Results: Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C.elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels.

Conclusion: We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia.
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http://dx.doi.org/10.1136/jmedgenet-2013-101542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133931PMC
August 2013

Regulation of aromatase expression in breast cancer treated with anastrozole neoadjuvant therapy.

Exp Ther Med 2013 Mar 24;5(3):902-906. Epub 2012 Dec 24.

Cancer Genomics Laboratory, Fondazione Edo ed Elvo Tempia Valenta, Biella;

Aromatase inhibitors (AIs), such as anastrozole, are established in the treatment of hormone-dependent breast cancer. However, ∼20% of patients with hormone receptor-positive breast tumors treated with anastrozole do not respond and it remains impossible to accurately predict sensitivity. Since polymorphisms in the aromatase gene may influence the response to inhibitory drugs, we evaluated the presence of rs6493497 and rs7176005 polymorphisms (mapping in the 5'-flanking region of the CYP19A1 gene coding for the aromatase protein) in a cohort of 37 patients with postmenopausal breast cancer who received three-month neoadjuvant treatment with anastrozole. We then investigated any association of the polymorphisms with changes in aromatase mRNA expression change and/or response to treatment. We also analyzed five miRNAs computationally predicted to target aromatase, to observe any association between their expression and sensitivity to anastrozole. Three samples carried the two polymorphisms and the remaining samples were wild-type for both, however, no association with response or with aromatase mRNA basal expression level or expression difference after therapy was observed. Polymorphic samples that were resistant to anastrozole showed no change or decrease in aromatase expression following AI treatment, whereas an increase in expression was observed for the polymorphic responsive samples. No statistically significant correlation was observed between miRNA and aromatase mRNA expression, or with response to anastrozole neoadjuvant treatment. These data indicate that the polymorphisms analyzed are not involved in aromatase activity and that other epigenetic mechanisms may regulate aromatase protein expression.
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http://dx.doi.org/10.3892/etm.2012.878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570232PMC
March 2013

Life-threatening tumors of the heart in fetal and postnatal age.

J Pediatr 2013 May 7;162(5):964-9.e1. Epub 2012 Dec 7.

Department of Anatomic Pathology, University Hospital, Pisa, Italy.

Objectives: To evaluate the role of histology in diagnosis and management of biologically benign heart tumors causing life-threatening symptoms and even death in children and fetuses. The clinical impact of a multidisciplinary approach including 2-D echocardiography, histology, genetics, and cardiac surgery has not yet been fully elucidated.

Study Design: Forty-one consecutive antenatal (n = 17) or postnatal (n = 24) detected cardiac masses were evaluated by 2-D echocardiography (in alive patients) or at autopsy, and 12/41 cases with definite histologic diagnosis of primary and benign cardiac tumor were entered in this study.

Results: Rhabdomyomas (n = 6), hemangiomas (n = 3), central fibrous body chondroma (n = 1), fibroma (n = 1), or left atrial myxoma (n = 1) were histologically diagnosed in 4 fetuses and in 8 children. Death occurred in 6 patients showing diffuse or infiltrative tumors, 2/6 experiencing intrauterine death or sudden and unexpected infant death. Seven patients underwent surgery, 4/7 are alive and well at >5 years follow-up, whereas 3 deaths followed partial tumor resection. Two fetuses with extensive tumor/s were aborted. Tuberous sclerosis complex gene mutations were seen in patients with rhabdomyomas.

Conclusions: Histology represents the best diagnostic approach in life-threatening pediatric cardiac tumors allowing definite diagnosis in cases other than rhabdomyoma and in sudden deaths, influencing clinical management and counselling. 2-D echocardiography remains the main tool for early clinical diagnosis and follow-up. A multidisciplinary approach is advisable because of rarity, difficult management, and possible associations with inheritable diseases.
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http://dx.doi.org/10.1016/j.jpeds.2012.10.055DOI Listing
May 2013

A peculiar mutation in the DNA-binding/dimerization domain of NFIX causes Sotos-like overgrowth syndrome: a new case.

Gene 2012 Dec 13;511(1):103-5. Epub 2012 Sep 13.

Unità Operativa di Genetica medica, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

The Nuclear Factor I-X (NFIX) is a member of the nuclear factor I (NFI) family proteins, which are implicated as site-specific DNA-binding proteins and is deleted or mutated in a subset of patients with Sotos-like overgrowth syndrome and in patients with Marshall-Smith syndrome. We evaluated an additional patient with clinical features of Sotos-like syndrome by sequencing analysis of the NFIX gene and identified a 21 nucleotide in frame deletion predicting loss of 7 amino acids in the DNA-binding/dimerization domain of the NFIX protein. The deleted residues are all evolutionally conserved amino acids. The present report further confirms that mutations in DNA-binding/dimerization domain cause haploinsufficiency of the NFIX protein and strongly suggests that in individuals with Sotos-like features unrelated to NSD1 changes genetic testing of NFIX should be considered.
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http://dx.doi.org/10.1016/j.gene.2012.08.040DOI Listing
December 2012
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