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  • Author: Luciani R Carvalho x
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Fernanda A Correa Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Ericka B Trarbach Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Cintia Tusset Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Ana Claudia Latronico Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Luciana R Montenegro Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Luciani R Carvalho Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Marcela M Franca Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Aline P Otto Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Everlayny F Costalonga Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Vinicius N Brito Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Ana Paula Abreu Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Mirian Y Nishi Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Alexander A L Jorge Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Ivo J P Arnhold Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Yisrael Sidis Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Nelly Pitteloud Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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Berenice B Mendonca Unidade de Endocrinologia do Desenvolvimento, Unidade de Endocrinologia Genética, Centre Hospitalier Universitaire Vaudois (CHUV), Division of Endocrinology, Laboratório de Hormônios e Genética Molecular LIM42

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The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2 + pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.

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Marilena Nakaguma Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Fernanda A Correa Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Lucas S Santana Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Anna F F Benedetti Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Ricardo V Perez Serviço de Endocrinologia, Hospital do Servidor Público Estadual de São Paulo, Instituto de Assistência Médica ao Servidor Público Estadual (HSPE-IAMSPE), São Paulo, Brasil

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Martha K P Huayllas Hospital de Transplantes Euryclides de Jesus Zerbini, São Paulo, Brasil

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Mirta B Miras Hospital de Niños Santísima Trinidad, Cordoba, Argentina

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Mariana F A Funari Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Antonio M Lerario Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Berenice B Mendonca Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Luciani R S Carvalho Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Alexander A L Jorge Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Ivo J P Arnhold Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

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Aim

Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism.

Methods

Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel.

Results

We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A].

Conclusions

Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

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Nathalia G B P Ferreira Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Joao L O Madeira Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Peter Gergics Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Renata Kertsz Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Juliana M Marques Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Nicholas S S Trigueiro Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Anna Flavia Figueredo Benedetti University of Michigan Medical School, Department of Human Genetics, Ann Arbor, Michigan, United States

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Bruna V Azevedo Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Bianca H V Fernandes Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
Universidade de São Paulo, Zebrafish Facility, São Paulo, São Paulo, Brazil

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Debora D Bissegatto Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Isabela P Biscotto Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Qing Fang Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Qianyi Ma Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Asye B Ozel Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Jun Li Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Sally A Camper Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil

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Alexander A L Jorge Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Berenice B Mendonça Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Ivo J P Arnhold Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Luciani R Carvalho Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

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Context

Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.

Objectives

The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.

Design

Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing.

Results

One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected.

Conclusion

A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.

Significance statement

A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.

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