Population medical genetics: translating science to the
community

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Abstract

Rare genetic disorders are currently in the spotlight due to the elevated number of different conditions and significant total number of affected patients. The study of these disorders is extremely helpful for the elucidation of physiological processes related with complex disorders. Isolated populations are instrumental for the study of genetic disorders, considering their homogeneity and high proportion of affected patients in a small geographic area. These favorable conditions lead to the creation of a new discipline, known as “population medical genetics”, which integrates medical genetics, population genetics, epidemiological genetics and community genetics. In order to develop practical activities in this new discipline, the National Institute of Population Medical Genetics (INaGeMP) was created in 2008 in Brazil. INaGeMP has developed several tools and funded numerous research activities. In this review, we highlight three successful projects developed in the first 10 years of INaGeMP activities (2008-2018): a newborn screening pilot study for MPS VI in Northeast Brazil, the study of Machado-Joseph disease in Brazilian families with Azorian ancestry, and the high twinning rate in a small town in southern Brazil. The results of these projects in terms of scientific output and contributions to the affected communities highlight the success and importance of INaGeMP.

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Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report

Natalia Mejía-Gaviria, Helena Gil-Peña, Eliecer Coto … (2010)

Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder (OMIM #241530), characterized by decreased renal phosphate reabsorption that leads to hypophosphatemia, rickets, and bone pain; hypophosphatemia is believed to stimulate 1,25 dihydroxyvitamin D synthesis which, in turn, results in hypercalciuria. Hereditary hypophosphatemic rickets with hypercalciuria is caused by loss-of-function in the type 2c sodium phosphate cotransporter encoded by the SLC34A3 gene. This report shows a family with a non-previously identified mutation in the SLC34A3 gene and exhibiting mild and different manifestations of HHRH. The probandus had hypophosphatemia, elevated serum 1,25 dihydroxyvitamin D concentrations, high serum alkaline phosphatase levels, hypercalciuria and nephrocalcinosis. The other members of the family presented some of these alterations: the mother, hypercalciuria and high 1,25 dihydroxyvitamin D concentrations; the son, hypercalciuria, high 1,25 dihydroxyvitamin D values and elevated alkaline phosphatases; the father, high alkaline phosphatases. The genetic analysis revealed the existence of a single mutation (G78R) in heterozygosis in the SLC34A3 gene in the probandus, her mother and her brother, but not in the father. These findings suggest that he mutation in heterozygosis likely gave rise to a mild phenotype with different penetrance in the three relatives and also indicates that the elevation of 1,25 dihydroxyvitamin D does not result from hypophosphatemia. Thus, this family raises some issues on the transmission and pathophysiology of hereditary hypophosphatemic rickets with hypercalciuria.

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Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility

Hamdi Mbarek, Stacy Steinberg, Dale R. Nyholt … (2016)

Spontaneous dizygotic (DZ) twinning occurs in 1%–4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB , p = 1.54 × 10 −9 , and rs17293443 in SMAD3 , p = 1.57 × 10 −8 ) and replicated (p = 3 × 10 −3 and p = 1.44 × 10 −4 , respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3 , the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.

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Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes.

Raphael Machado de Castilhos, Gabriel Furtado, Tailise Conte Gheno … (2014)

This study describes the frequency of spinocerebellar ataxias and of CAG repeats range in different geographical regions of Brazil, and explores the hypothetical role of normal CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, and ATXN7 genes on age at onset and on neurological findings. Patients with symptoms and family history compatible with a SCA were recruited in 11 cities of the country; clinical data and DNA samples were collected. Capillary electrophoresis was performed to detect CAG lengths at SCA1, SCA2, SCA3/MJD, SCA6, SCA7, SCA12, SCA17, and DRPLA associated genes, and a repeat primed PCR was used to detect ATTCT expansions at SCA10 gene. Five hundred forty-four patients (359 families) were included. There were 214 SCA3/MJD families (59.6 %), 28 SCA2 (7.8 %), 20 SCA7 (5.6 %), 15 SCA1 (4.2 %), 12 SCA10 (3.3 %), 5 SCA6 (1.4 %), and 65 families without a molecular diagnosis (18.1 %). Divergent rates of SCA3/MJD, SCA2, and SCA7 were seen in regions with different ethnic backgrounds. 64.7 % of our SCA10 patients presented seizures. Among SCA2 patients, longer ATXN3 CAG alleles were associated with earlier ages at onset (p < 0.036, linear regression). A portrait of SCAs in Brazil was obtained, where variation in frequencies seemed to parallel ethnic differences. New potential interactions between some SCA-related genes were presented.

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Author and article information

Journal

Journal ID (nlm-ta): Genet Mol Biol

Journal ID (iso-abbrev): Genet. Mol. Biol

Journal ID (publisher-id): gmb

Title: Genetics and Molecular Biology

Publisher: Sociedade Brasileira de Genética

ISSN (Print): 1415-4757

ISSN (Electronic): 1678-4685

Publication date (Electronic): 11 April 2019

Publication date (Print): 2019

Volume: 42

Issue: 1 Suppl 1

Pages: 312-320

Affiliations

[ 1 ]Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

[ 2 ]Department of Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 3 ]Instituto Nacional de Ciência e Tecnologia de Genética Médica Populacional (INaGeMP), Porto Alegre, RS, Brazil

[ 4 ]Postgraduate Program in Medicine: Medical Sciences Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 5 ]APAE, Salvador, Brazil

[ 6 ]Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil

[ 7 ]Fundação Oswaldo Cruz (FIOCRUZ), Salvador, BA, Brazil

[ 8 ]Department of Pediatrics, Universidade Federal da Bahia, Salvador, BA, Brazi

[ 9 ]Department of Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 10 ]Genetics Identification Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

[ 11 ]Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 12 ]Postgraduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 13 ]Postgraduate Program in Celular and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 14 ]Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

[ 15 ]Prefeitura Municipal de Cândido Godói, Candido Godói, RS, Brazil

Author notes

Send correspondence to Francyne Kubaski. Medical Genetics Service - Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos, 90035-903 Porto Alegre, RS, Brazil. E-mail: fkubaski@ 123456udel.edu

Author information

Roberto Giugliani http://orcid.org/0000-0001-9655-3686

Maria Luiza Saraiva-Pereira http://orcid.org/0000-0003-3905-9563

Laura Bannach Jardim http://orcid.org/0000-0001-6907-5068

Lavínia Schuler-Faccini http://orcid.org/0000-0002-2428-0460

Francyne Kubaski http://orcid.org/0000-0002-9330-0154

Article

DOI: 10.1590/1678-4685-GMB-2018-0096

PMC ID: 6687347

PubMed ID: 30985854

SO-VID: 2111cc45-3383-49ae-a2da-5353cc1bac3f

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License information: This is an open-access article distributed under the terms oAssociate Editor: Carlos F. M. Menckf the Creative Commons Attribution License (type CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original article is properly cited.

History

Date received : 22 May 2018

Date accepted : 11 July 2018

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Population medical genetics: translating science to the community

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Most cited references 56

Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report

Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility

Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes.

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