Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci

Ledig, Susanne; Hiort, Olaf; Scherer, Gerd; Hoffmann, M.; Wolff, Gerhard; Morlot, Susanne; Kuechler, Alma; Wieacker, Peter

doi:10.1093/humrep/deq167

Cited by 97 publications

(113 citation statements)

References 53 publications

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“…The function of the corresponding proteins is still unknown. Because of all these findings, it is very unlikely that the duplications Previously, we have reported a larger deletion of w103 kb disturbing exons 1 and 2 of DMRT1 in a patient with a complete form of XY gonadal dysgenesis (22). It is not clear why one deletion (present case) is associated with ovotesticular DSD and the other deletion with XY gonadal dysgenesis.…”

Section: Discussionmentioning

confidence: 71%

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Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

Ledig¹,

Hiort²,

Wünsch³

et al. 2012

European Journal of Endocrinology

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Objective: Ovotesticular disorder of sexual development (DSD) is an unusual form of DSD, characterized by the coexistence of testicular and ovarian tissue in the same individual. In a subset of patients, ovotesticular DSD is caused by 46,XX/46,XY chimerism or mosaicism. To date, only a few monogenetic causes are known to be associated with XX and XY ovotesticular DSD. Design and methods: Clinical, hormonal, and histopathological data, and results of high-resolution array-comparative genomic hybridization (CGH) were obtained from a female patient with 46,XY ovotesticular DSD with testicular tissue on one side and an ovary harboring germ cells on the other. Results obtained by array-CGH were confirmed by RT-quantitative PCR. Results: We detected a deletion of w35 kb affecting exons 3 and 4 of the DMRT1 gene in a female patient with 46,XY ovotesticular DSD. To the best of our knowledge, this is the smallest deletion affecting DMRT1 presented to this point in time. Conclusions: We suggest that haploinsufficiency of DMRT1 is sufficient for both XY gonadal dysgenesis and XY ovotesticular DSD. Furthermore, array-CGH is a very useful tool in the molecular diagnosis of DSD.

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Section: Discussionmentioning

confidence: 71%

“…Mutational analysis in all three genes resulted in only two potential pathogenic mutations of DMRT1 (20,21). Recently, we showed that deletions of only DMRT1 can cause XY gonadal dysgenesis (22).…”

Section: Introductionmentioning

confidence: 99%

Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

Ledig¹,

Hiort²,

Wünsch³

et al. 2012

European Journal of Endocrinology

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“…It is also becoming a powerful tool in the discovery of disease genes, identification of new syndromes, and delineation of known deletion/duplication syndromes, known as genomic disorders. In the field of endocrinology, genome-wide analysis of CNVs has been evaluated as a tool to identify genetic causes in several clinical conditions, including premature ovarian failure (6), severe early-onset obesity (7), congenital hypothyroidism and thyroid dysgenesis (8), ambiguous genitalia (9), skeletal defects with growth impairment (10), and Silver-Russell syndrome (11). Two recent studies have demonstrated the presence of causative and possible pathogenic CNVs in short-stature children (12,13).…”

Section: Introductionmentioning

confidence: 99%

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Canton

Costa

Rodrigues

et al. 2014

European Journal of Endocrinology

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Background: The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. Objective: To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. Patients and methods: A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. Results: In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Conclusion: Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.

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“…Although comparative genomic hybridization (CGH) and array CGH techniques, powerful tools for the detection of minor chromosomal imbalances, have been used to investigate 46,XY GD patients, DMRT1 deletion has rarely been identified in patients without syndromic features [9,20].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, the deletion of DMRT1 has been rarely associated with the presence of isolated gonadal dysgenesis in 46,XY DSD patients [8,9].…”

Section: Introductionmentioning

confidence: 99%

Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis

Machado¹,

Silva²,

Costa³

et al. 2012

European Journal of Medical Genetics

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Array-CGH analysis in patients with syndromic and non-syndromic XY gonadal dysgenesis: evaluation of array CGH as diagnostic tool and search for new candidate loci

Abstract: This study shows that array comparative genomic hybridization (CGH) analysis is a useful tool for the molecular diagnosis of XY-GD as well as for the identification of potential candidate genes involved in male sexual development.

Cited by 97 publications

References 53 publications

Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways

Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis

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