Kent D. McKelvey

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.To promote standardized reporting of actionable information from clinical genomic sequencing, in 2013, the American College of Medical Genetics and Genomics (ACMG) published a minimum list of genes to be reported as incidental or secondary findings. The goal was to identify and manage risks for selected highly penetrant genetic disorders through established interventions aimed at preventing or significantly reducing morbidity and mortality. The ACMG subsequently established the Secondary Findings Maintenance Working Group to develop a process for curating and updating the list over time. We describe here the new process for accepting and evaluating nominations for updates to the secondary findings list. We also report outcomes from six nominations received in the initial 15 months after the process was implemented. Applying the new process while upholding the core principles of the original policy statement resulted in the addition of four genes and removal of one gene; one gene did not meet criteria for inclusion. The updated secondary findings minimum list includes 59 medically actionable genes recommended for return in clinical genomic sequencing. We discuss future areas of focus, encourage continued input from the medical community, and call for research on the impact of returning genomic secondary findings.Genet Med 19 2, 249–255.

Low bone turnover and low BMD in Down syndrome: effect of intermittent PTH treatment.

Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients’ age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population.

Adult-onset psychosis and clinical genetics: a case of Phelan-McDermid syndrome.

The patient is a 38-year-old woman previously diagnosed with cerebral palsy, major depressive disorder with psychotic features, general anxiety disorder, and schizophrenia with catatonia. She has a history of developmental delay, hypotonia, and seizure-like activity since childhood. Although she has moderate mental retardation (IQ: 51) she is verbal, friendly, and completed high school (special education). General functioning, mood, and behavior were stable into adulthood until her first psychiatric hospitalization at age 32. She began having behavioral regression and decline in skills including bathing, dressing, and feeding. For periods of weeks she became nonverbal, confused, detached, and incontinent. She would often stare at her hands, at times shaking or screaming, and refuse to eat.

Aneuploidy and Skeletal Health

The normal human chromosome complement consists of 46 chromosomes comprising 22 morphologically different pairs of autosomes and one pair of sex chromosomes. Variations in either chromosome number and/or structure frequently result in significant mental impairment and/or a variety of other clinical problems, among them, altered bone mass and strength. Chromosomal syndromes associated with specific chromosomal abnormalities are classified as either numerical or structural and may involve more than one chromosome. Aneuploidy refers to the presence of an extra copy of a specific chromosome, or trisomy, as seen in Down’s syndrome (trisomy 21), or the absence of a single chromosome, or monosomy, as seen in Turner syndrome (a single X chromosome in females: 45, X). Aneuploidies have diverse phenotypic consequences, ranging from severe mental retardation and developmental abnormalities to increased susceptibility to various neoplasms and premature death. In fact, trisomy 21 is the prototypical aneuploidy in humans, is the most common genetic abnormality associated with longevity, and is one of the most widespread genetic causes of intellectual disability. In this review, the impact of trisomy 21 on the bone mass, architecture, skeletal health, and quality of life of people with Down syndrome will be discussed.

Male infertility associated with hereditary leiomyomatosis and renal cell carcinoma.

OBJECTIVE To report a novel association between a cancer predisposition syndrome (hereditary leiomyomatosis and renal cell carcinoma [HLRCC]) and male infertility. DESIGN Case report. SETTING University medical center adult genetics clinic. PATIENT(S) A 31-year-old male of Chinese ancestry referred for evaluation of immotile sperm. INTERVENTION(S) Physical examination, family history assessment, genetic testing, and cancer screening. MAIN OUTCOME MEASURE(S) Genetic testing results. RESULT(S) Physical exam: cutaneous leiomyomata on the upper back and left arm. Family history: the patient has a sister with uterine leiomyomata. Genetic testing revealed a mutation in the fumarate hydratase gene, which codes for an enzyme (fumarase) that has previously been implicated in sperm number and motility. More recently, heterozygous mutations in this gene have been associated with HLRCC. However, male infertility is not a recognized manifestation of this condition. CONCLUSION(S) A comprehensive medical (including family) history and physical examination are important when evaluating male infertility. Genetics consultation enabled our patient and his family to begin appropriate cancer screening and provided reproductive options, including prenatal/preimplantation diagnosis. Further studies of the relationship between fumarase, HLRCC, and male infertility are needed to provide accurate counseling to families and to better understand genotype-phenotype correlations.

438Genetic Variants Associated with the Development of Clostridium Difficile Infection during Autologous Stemcell Transplantation

Difficile Infection during Autologous Stemcell Transplantation Senu Apewokin, MD; Elizabeth Coleman, PhD; Carol Enderlin, PhD; Julia Goodwin, PhD; Jeannette Lee, PhD; Stephen Erickson, PhD; Kent Mckelvey, MD, PhD; Vinay Raj, PhD; Naveen Sanath Kumar, MD; Zhou Daohong, PhD; The Myeloma Institute for Research and Therapy/University of Arkansas for Medical Sciences, Little Rock, AR; University of Arkansas for Medical Sciences, Little Rock, AR

Host genetic susceptibility to Clostridium difficile infections in patients undergoing autologous stem cell transplantation: a genome-wide association study

BackgroundClostridium difficile infection (CDI) is the most common hospital-acquired infection. Unfortunately, genes that identify CDI-susceptible patients have not been well described. We performed a genome-wide association study (GWAS) to determine genetic variants associated with the development of CDI.MethodsA cohort study of Caucasian patients undergoing autologous stem cell transplantation for multiple myeloma was performed. Patients were genotyped using Illumina® Whole Genome Genotyping Infinium chemistry. We then compared CDI-positive to CDI-negative patients using logistic regression for baseline clinical factors and false discovery rate (FDR) for genetic factors [single nucleotide polymorphisms (SNPs)]. SNPs associated with CDI at FDR of p < 0.01 were then incorporated into a logistic regression model combining clinical and genetic factors.ResultsOf the 646 patients analyzed (59.7% male), 57 patients were tested CDI positive (cases) and were compared to 589 patients who were tested negative (controls). Hemoglobin, albumin, and hematocrit were lower for cases (p < 0.05). Eight SNPs on five genes (FLJ16171, GORASP2, RLBP1L1, ASPH, ATP7B) were associated with CDI at FDR p < 0.01. In the combined clinical and genetic model, low albumin and three genes RLBP1L1, ASPH, and ATP7B were associated with CDI.ConclusionLow serum albumin and genes RLBP1L1 and ASPH located on chromosome 8 and ATP7B on chromosome 13 were associated with CDI. Of particular interest is ATP7B given its copper modulatory role and the sporicidal properties of copper against Clostridium difficile.

Clinical Genetics and Heritable Parathyroid Disease: Monogenic Disorders

Germline genetic tests can be extremely helpful for clinical diagnosis of patients and their families when a known deleterious change is found, but there are many reasons why gene testing and interpretation is not straightforward. This chapter pertains to monogenic conditions in which the genetic contribution to a parathyroid disorder is well-established. These disorders include: familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome and parathyroid carcinoma and multiple endocrine neoplasia types 1, 2, and 4.