A rare mutation in SMAD9 associated with high bone mass identifies the SMAD-dependent BMP signalling pathway as a potential anabolic target for osteoporosis

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (P-GWAS = 6 x 10(-16); P-GENE = 8 x 10(-17)). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. (c) 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research

NAD deficiency, congenital malformations, and niacin supplementation

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice

Genetic testing in Parkinson's disease

Since my colleagues and I submitted a manuscript on the complexities of genetic testing in Parkinson's disease (PD),1 an important gene discovery has been made. The gene located at the PARK8 locus (12q), which was initially discovered in a Japanese family,2 has been identified. At the end of 2004, two research groups independently isolated the gene LRRK2 and recognized seven missense mutations in autosomal dominant families from England, Spain, Germany, and Canada.3, 4..

Prevalence of Parkinson's disease in populations of African ancestry: A review

This article is free to read on the publishers website There have been a number of studies looking at the prevalence of Parkinson's disease (PD) in different racial and geographical populations. Some of the earliest studies suggested a difference in the prevalence of PD in African Americans as compared with Caucasians. As such a difference would have important implications for healthcare and research into the etiology of PD, we undertook a review of published studies to determine whether evidence suggested that such a difference exists. We reviewed 20 studies that looked at incidence, prevalence, and percentages of neurology patients with PD and Parkinsonism in Africa and in African-American populations. Two of these were door-to-door studies that relied on questionnaires for initial ascertainment, another was performed by review of outpatient records of a large health maintenance organization, while the remainder were based on hospital admissions, diagnosis in the community, or death certificate reports. In the aggregate, these studies suggest PD may be less frequent among Africans and African Americans than among Caucasians, although the most well-designed study showed only a statistically insignificant reduction in the prevalence of PD among African Americans. Although an apparently lower disease frequency among people of African origin may have a basis in the pathobiology of the disease, nearly all of these studies were vulnerable to a variety of ascertainment biases, and many lacked stringent application of diagnostic criteria applied by specialists trained in movement disorders. We conclude that a difference in the prevalence of PD and Parkinsonism between black and other populations is unproven and will require additional well-designed studies to determine if previously reported ethnic differences in disease prevalence are real

The emerging field of polygenic risk scores and perspective for use in clinical care

Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes, and cancer. Genome wide association studies (GWAS) have been invaluable in identifying single nucleotide polymorphisms (SNPs), associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs; guiding therapeutic interventions; refining risk for families at high-risk; and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also discussed

Education about genetic testing for breast cancer susceptibility: Patient preferences for a computer program or genetic counselor

The purpose of this study was to describe and compare patient preferences for a genetic counselor or an interactive computer program for various components of genetic education and counseling for breast cancer susceptibility. As part of a randomized intervention study on genetics education and counseling for breast cancer risk, 29 women at moderate risk were educated by both a genetic counselor and an interactive computer program. After both educational interventions, participants completed Likert-style and open-ended questionnaires about what they liked most and least about each intervention, and whether they preferred the counselor or computer for a variety of tasks. Participants were largely satisfied with both the computer program and the genetic counselor. A majority preferred the genetic counselor for addressing their concerns, discussing options and alternatives, being sensitive to emotional concerns, helping to make a decision, being a good listener, assuring understanding, helping to make a good choice, helping to understand genes and breast cancer, telling them what they needed to know, being respectful, setting a relaxed tone, and putting them at ease. However, a majority of the women either preferred the computer program or were neutral about allowing patients to learn at their own pace, helping to avoid embarrassment, making good use of time, explaining genes and breast cancer, and treating the patient as an adult. Qualitative analysis of open-ended questions affirmed that patients valued the personal interactions with the counselors, and liked having their specific questions answered. They liked that the computer was self-paced, informative and private, and could be used without causing embarrassment. We concluded that a computer literate, mostly white group of women at moderate risk for inherited susceptibility to breast cancer preferred interacting with a genetic counselor for personal, individualized components of the genetic counseling process, but accepted or preferred a computer program for being self-paced, private, and informative. By incorporating such a computer program into the genetic education process, it is possible that genetic counselors would be able to spend more time performing the personal, individualized components of genetic counseling

Knowledge and attitudes towards genetic testing in those affected with Parkinson’s disease

Advances in genetic tests provide valuable information for clinicians and patients around risks and inheritance of Parkinson’s Disease (PD); however, questions arise whether those affected or at risk of PD will want genetic testing, particularly given that there are no preventive or disease-modifying therapies currently available. This study sought to determine knowledge and attitudes toward genetic testing for those affected with PD. A cross-sectional study was undertaken using a standardized questionnaire with six multi-choice genetic knowledge and 17 multi-choice attitude items. Participants were selected from a registry of people affected with PD living in Queensland, Australia. Half of the selected index cases had a family history of PD. Ordinal regression was used to evaluate the association between support for genetic testing and demographic, knowledge, and other attitudinal factors. The level of genetic knowledge was relatively low (37 % correct responses). The vast majority supported diagnostic testing (97 %) and 90 % would undertake a genetic test themselves. Support for predictive was lower (78 %) and prenatal genetic testing had the least support (58 %). Benefits of testing were identified as the ability to know the child’s risk, seek therapies, and helping science with finding a cure. Concerns about genetic testing included potential emotional reactions and test accuracy. Genetic knowledge was not significantly associated with attitudes towards genetic testing. Patients with PD have strong interest in genetic testing for themselves with support for diagnostic testing but less support for predictive and prenatal testing. Genetic knowledge was unrelated to testing attitudes