Darci L Sternen

Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources.

Fanconi anemia-like presentation in an infant with constitutional deletion of 21q including the RUNX1 gene†

We describe a newborn female with a de novo interstitial deletion of chromosome 21q21.1‐22.12 including the RUNX1 gene who had developmental delay, multiple congenital anomalies, tetralogy of Fallot, anemia, and chronic thromobocytopenia requiring frequent platelet transfusions from birth. Because of her physical and hematologic abnormalities, she was tested for Fanconi anemia (FA). Lymphocytes and fibroblasts from this patient demonstrated increased chromosome breakage with exposure to the clastogen mitomycin C, but not, in contrast to most FA patients, to diepoxybutane. Further testing by Western analysis and complementation testing did not show a defect in the function of known Fanconi proteins. Her constitutional deletion was later found to span 13.2 Mb by chromosome microarray analysis, encompassing the RUNX1 gene that has been implicated in thrombocytopenia and predisposition to acute myelogenous leukemia (AML) when in the haploinsufficient state. We compare her phenotype to other individuals with similar 21q deletions and thrombocytopenia, as well as those with FA. We suggest that deletion of RUNX1 or another critical gene within the deleted region may result in chromosomal instability similar to that seen in FA.

AB030. The evolving role of genetic counseling

Master level genetic counseling training programs have existed in the United States of America (USA) since 1969. There are now 31 programs to train genetic counselors in the USA, 4 programs in Canada, and 2 programs in Australia. These programs generally train non-medical health professionals (individuals with a BSc or MSc). There are 25 additional programs worldwide, training a combination of physicians, nurses, and non-medical health professionals. Students in the USA, Canada and Australia are required take a certification examination and licensure privileges dependent on the rules of a specific state or providence. The roles of genetic counselors have evolved with genetic medicine. Initial work of genetic counselors involved predominately direct patient care in the prenatal, pediatric and adult genetic clinics. When a hereditary component to cancer was recognized, there was an increasing need for genetic counselors for the consultation and results interpretation in cancer care. With the completion of the Human Genome Project in 2003 and the decreasing cost of next generation sequencing, there has been a plethora of molecular genetic studies that have been available to the genetics provider. Many genetic counselors have migrated to the laboratory setting to assist providers with the selection and interpretation of laboratory studies. With this great expansion of genomic testing available, there has been a concomitant identification of genomic alterations of uncertain significance that require extensive evaluation to determine clinical significance. Genetic counselors have been essential for this work in both the research and clinical setting. Genetic counselors have been recognized as one of the most needed health care professionals in the USA in the next decade. The role of the genetic counselors in emerging countries is complex with the simultaneous need for direct patient care and the support of laboratory services. The development of programs in emerging countries will need to train students with a broad spectrum of skills to include both direct clinical care and to understanding the current complexities of genomic testing. Anticipating social and emotional needs of multiple populations within a country will be an ongoing challenge. Commitment of trained professionals from established clinical genetic programs can facilitate educational support for programs in emerging countries. With this Asia Pacific Meeting, there was a preconference to support genetic counseling in the region. The results of the questionnaire presented to the 70 attendants of this pre-conference will be presented with projections of future needs for genetic counseling training in this region.