Background: Genetic hypothyroidism presents a heterogeneous genetic inheritance: single allele mutation in genes with recessive pattern (pseudodominance), digenic inheritance and one phenotype/one mutation association were all observed, in particular in case of mild or complex phenotypes. Therefore it is necessary to screen multiple genes in order to identify the genetic defect and to help clinical management of these patients and families. Objective and hypotheses:TSH receptor gene (TSHR) is the more frequent mutated gene in genetic hypothyroidism, so this represent the first target to be tested. If THSR gene sequence is normal, copy number determination of TSHR exons may be performed by MLPA analysis, together with other hypothyroidism genes. If hypothyroidism genes have normal dosage, their complete sequencing may be considerate. Methods: From a large series of patients with hypothyroidism already screened for point mutation in TSHR gene by sequencing, we selected 22 patients with thyroid hypoplasia. 9 pts. presented congenital hypothyroidism and were positive at neonatal screening, 13 pts. were diagnosed as subclinical hypothyroidism (TSH>4.2 mU/liter) after neonatal period. To complete the search of causative mutations we performed copy number determination on genomic DNA from peripheral blood by MLPA analysis, with probes for TSHR gene and PAX8, TPO, FOXE1 and NKX2.1 genes. Results: A deletion of TSHR gene exon 1 was identified in one allele in a patient, he was 6 yrs. old at first evaluation and presented TSH level up to normal range in more than two tests. Conclusions: Our results confirmed the primary role of TSHR gene mutations in hypothyroidism and the necessity of copy number determination of hypothyroidism genes in diagnostic steps. We intend to extend the MLPA analysis in all the patients with suspected genetic hypothyroidism, and to proceed with PAX8 gene sequencing in negative cases to improve the mutation detection of this heterogeneous disease

Copy number determination of hypothyroidism genes by MLPA analysis in patients with hypothyroidism and thyroid hypoplasia

NICOLETTI, ANNALISA;CASSIO, ALESSANDRA;MENABO', SOARA;MAZZANTI, LAURA;
2013

Abstract

Background: Genetic hypothyroidism presents a heterogeneous genetic inheritance: single allele mutation in genes with recessive pattern (pseudodominance), digenic inheritance and one phenotype/one mutation association were all observed, in particular in case of mild or complex phenotypes. Therefore it is necessary to screen multiple genes in order to identify the genetic defect and to help clinical management of these patients and families. Objective and hypotheses:TSH receptor gene (TSHR) is the more frequent mutated gene in genetic hypothyroidism, so this represent the first target to be tested. If THSR gene sequence is normal, copy number determination of TSHR exons may be performed by MLPA analysis, together with other hypothyroidism genes. If hypothyroidism genes have normal dosage, their complete sequencing may be considerate. Methods: From a large series of patients with hypothyroidism already screened for point mutation in TSHR gene by sequencing, we selected 22 patients with thyroid hypoplasia. 9 pts. presented congenital hypothyroidism and were positive at neonatal screening, 13 pts. were diagnosed as subclinical hypothyroidism (TSH>4.2 mU/liter) after neonatal period. To complete the search of causative mutations we performed copy number determination on genomic DNA from peripheral blood by MLPA analysis, with probes for TSHR gene and PAX8, TPO, FOXE1 and NKX2.1 genes. Results: A deletion of TSHR gene exon 1 was identified in one allele in a patient, he was 6 yrs. old at first evaluation and presented TSH level up to normal range in more than two tests. Conclusions: Our results confirmed the primary role of TSHR gene mutations in hypothyroidism and the necessity of copy number determination of hypothyroidism genes in diagnostic steps. We intend to extend the MLPA analysis in all the patients with suspected genetic hypothyroidism, and to proceed with PAX8 gene sequencing in negative cases to improve the mutation detection of this heterogeneous disease
Annalisa Nicoletti; Alessandra Cassio; Ilaria Bettocchi; Soara Menabò; Angela Rizzello; Giuseppe A. Cangemi; Laura Mazzanti; Lilia Baldazzi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/390961
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