Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes

Correa, Fernanda A.; Jorge, Alexander A L; Nakaguma, Marilena; Canton, Ana P. M.; Costa, Silvia Souza da; Funari, Mariana F A; Lerário, Antônio Marcondes; França, Marcela M.; Carvalho, Luciani R.; Krepischi, Ana Cristina Victorino; Arnhold, Ivo J.P.; Rosenberg, Carla; Mendonca, Berenice B.

doi:10.1111/cen.13535

Cited by 12 publications

(10 citation statements)

References 19 publications

(27 reference statements)

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“…Here, we took advantage of our 5-year experience as a largescale sequencing core facility to build a representative local genomic database for the southeastern Brazilian population, SELAdb. Although many individuals included in SELAdb are patients or family members with rare Mendelian disorders, contributing to the identification of novel diseasecausing variants (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), our analyses demonstrate that it adequately represents our local patient population. Through ancestry analysis, we observed that the population captured by SELAdb bears diverse genetic influences, which are characteristic of the admixed southeastern Brazilian population, similar to previous reports (3).…”

Section: ' Discussionmentioning

confidence: 98%

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

Lerário

Mohan

Montenegro

et al. 2020

Clinics

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OBJECTIVES: High-throughput sequencing of genomes, exomes, and disease-focused gene panels is becoming increasingly common for molecular diagnostics. However, identifying a single clinically relevant pathogenic variant among thousands of genetic polymorphisms is a challenging task. Publicly available genomic databases are useful resources to filter out common genetic variants present in the population and enable the identification of each disease-causing variant. Based on our experience applying these technologies at Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil, we recognized that the Brazilian population is not adequately represented in widely available genomic databases. METHODS: Here, we took advantage of our 5-year experience as a high-throughput sequencing core facility focused on individuals with putative genetic disorders to build a genomic database that may serve as a more accurate reference for our patient population: SELAdb. RESULTS/CONCLUSIONS: Currently, our database comprises a final cohort of 523 unrelated individuals, including patients or family members managed by different clinics of HCFMUSP. We compared SELAdb with other publicly available genomic databases and demonstrated that this population is very heterogeneous, largely resembling Latin American individuals of mixed origin, rather than individuals of pure European ancestry. Interestingly, exclusively through SELAdb, we identified a spectrum of known and potentially novel pathogenic variants in genes associated with highly penetrant Mendelian disorders, illustrating that pathogenic variants circulating in the Brazilian population that is treated in our clinics are underrepresented in other population databases. SELAdb is freely available for public consultation at: http://intranet.fm.usp.br/sela

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Section: ' Discussionmentioning

confidence: 98%

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

Lerário

Mohan

Montenegro

et al. 2020

Clinics

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“…Finalmente, en 2018, estudios realizados por Correa y sus colaboradores reportaron un paciente masculino de 16 años con evidencia de retraso en el desarrollo, discapacidad intelectual grave y una dismorfia facial, por lo cual el paciente depende de la atención de sus padres (18). Este paciente presenta, dos alteraciones cromosómicas terminales: una duplicación de 14.7 Mb de un segmento del brazo corto del cromosoma 2 (2p25.3p24.3) y una deleción de 4 Mb en el brazo largo del cromosoma 4 (4q35.1q35.2).…”

Section: Discussionunclassified

Presencia de duplicación 2p25.3 y síndrome de microdeleción 2q37.3 en un mismo individuo

2020

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El estudio del cromosoma 2 en los seres humanos ha permitido reconocer que su alteración, basada en una localización específica, puede conducir a diversas enfermedades asociadas. Mediante la identificación fenotípica, sustentada en el estudio molecular de hibridación genómica comparativa y un estudio bioinformático posterior, se detectó la presencia de una duplicación patogénica en la región cromosómica 2p25.3p24.3, relacionada con la afección de 36 genes. Adicionalmente, se identificó una deleción patogénica en la citobanda 2q37.3, relacionada con la afección de 36 genes. El análisis bioinformático demostró interacciones entre genes que explican características sintomatológicas. Esta es la primera vez que se presentan estas dos variantes en un mismo individuo. Ambas alteraciones se han asociado con retraso psicomotor moderado, autismo, neurohipófisis ectópica, aracnodactilia, cardiopatía congénita y alteraciones cardiovasculares. Se ha propuesto que la mutación hdac4 es la causante de la mayoría de las características del síndrome de microdeleción 2q37. El fenotipo clínico heterogéneo es el resultado del reordenamiento cromosómico encontrado, lo cual permite describir, interpretar y dar un tratamiento oportuno y dirigido a la paciente y la respectiva conserjería genética familiar. Finalmente, esta es la primera vez que se reporta este tipo específico de reordenamiento cromosómico.

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“…SNP array was performed as previously described ( Jee et al, 2017 ). SNP array data were analyzed for copy-number variations (CNVs) previously reported to be associated with congenital hypopituitarism ( Correa et al, 2018 ), as well as to confirm paternity and rule out parental consanguinity.…”

Section: Methodsmentioning

confidence: 99%

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

et al. 2021

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PurposeCongenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown.MethodsWe studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups.ResultsFirst, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband’s condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01).ConclusionOur findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

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Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes

Abstract: Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism.

Cited by 12 publications

References 19 publications

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

SELAdb: A database of exonic variants in a Brazilian population referred to a quaternary medical center in São Paulo

Presencia de duplicación 2p25.3 y síndrome de microdeleción 2q37.3 en un mismo individuo

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

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