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Syndromic cases of hemophilia B and morbid obesity due to contiguous gene deletions on Xq26.3-q27.2: unsuspected phenotype-genotype associations by bioinformatics and extensive clinical data mining
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  • Pamela Radic,
  • Miguel Abelleyro,
  • Betiana Ziegler,
  • Vanina Marchione,
  • Julian Nevado,
  • Pablo Lapunzina,
  • Gabriela Sciuccati,
  • Daniela Neme,
  • Liliana Rossetti,
  • Mariana Bonduel,
  • Carlos De Brasi
Pamela Radic
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Miguel Abelleyro
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Betiana Ziegler
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Vanina Marchione
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Julian Nevado
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz
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Pablo Lapunzina
Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz
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Gabriela Sciuccati
Hospital de Pediatría Prof Dr Juan P Garrahan Servicio de Hematología y Oncología
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Daniela Neme
Fundación de la Hemofilia Alfredo Pavlovsky.
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Liliana Rossetti
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Mariana Bonduel
Hospital de Pediatria Prof Dr Juan P Garrahan Servicio de Hematologia y Oncologia
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Carlos De Brasi
Instituto de Medicina Experimental (IMEX-CONICET/ANM)
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Abstract

Hemophilia B (HB) associates with pathogenic F9-variants. The literature showed that hemizygous deletions encompassing F9 and vicinal genes may express extra-phenotypes suggesting new causal relationships. Aim: Analyze the molecular basis of syndromic cases of HB, obesity (OB), severe global developmental delay (SGDD) and generalized hypotonia (GH). Whole F9-deletions were detected in 3 hemizygous probands with HB. Dense SNP-array and case-specific STS walking strategies allowed amplification and characterization of the deletion breakpoints. Bioinformatic/statistical analyses included data mining in HPO (Human Phenotype Ontology), OMIM, STRING (protein-protein interaction networks) databases and estimation of null-hypothesis-based Expected-values. Patients (cases#3-case#1) showed complete F9 deletions involving 0.16-4.34-Mb and 1-17 additional genes on Xq26.3-q27.2. Bioinformatic/statistical approaches revealed highly significant STRING-associations (P≤0.00115) between case#1/#2 common deleted genes (SOX3, FGF13, CXorf66) and those HPO associated with OB (20/343), GH (36/923) and SGDD (10/119). Only case#2 showed two extra-phenotypic abnormalities, anal atresia and pituitary hypothyroidism, and one extra-deleted gene, MAGEC2. Our bioinformatic/statistical approaches confirmed a previous involvement of SOX3 in OB suggesting additional roles in GH and SGDD, similar to FGF13 and CXorf66 (experimentally linked to POMGNT1, HPO-connected with all 3 phenotypes). Our findings highlight the importance to characterize X-chromosome deletion syndromes to unveil functional associations of the involved genomic regions.