No abstract

Genetic counseling for cystic fibrosis (CF) is challenged by intricate molecular mechanisms, complex phenotypes, and psychosocial needs. CFTR variant interpretation has become critical; this manuscript examines variant nomenclature and classes, as well as opportunities and challenges posed by genetic technologies and genotypedirected therapies. With postgraduate training in medical genetics and counseling, genetic counselors educate patients and families, facilitate testing and interpretation, and help integrate genetic information into diagnosis and treatment. They support families, ranging from carrier couples or new parents, to children understanding their disease, to adults with CF contemplating reproduction. The changing face of CF increasingly highlights the critical importance of genetic information to patients and their families. Genetic counselors are uniquely poised to translate this information in diagnostics and personalized care. Genetic counselors straddle molecular and clinical realms, helping patients adapt, plan, and gain access to appropriate therapies.

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein. Currently, over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease. The types of these pathogenic mutations are varied, often resulting in misfolding, or truncating of the AAT amino acid sequence, and improvements in sequencing technology are helping to identify known and novel genetic variants. However, due to the diversity and novelty of rare variants, the clinical significance of many is largely unknown. There is, therefore, a lack of guidance on how patients should be monitored and treated when the clinical significance of their variant combination is unclear or variable. Nevertheless, it is important that physicians understand the advantages and disadvantages of the different testing methodologies available to diagnose AATD. Owing to the autosomal inheritance of the genetic mutations responsible for AATD, genetic testing should be offered not only to patients at increased AATD risk (e.g. patients with chronic obstructive pulmonary disease), but also to relatives of those with an abnormal result. Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family. While stress/anxiety can arise from genetic diagnosis or confirmation of carrier status, there can be positive consequences to genetic testing, including improved lifestyle choices, directed medical care, and empowered family planning. As genetic testing technology grows and becomes more popular, testing without physician referral is becoming more prevalent, irrespective of the availability of genetic counseling. Therefore, the Alpha-1 Foundation offers genetic counseling, as well as other support and educational material, for patients with AATD, as well as their families and physicians, to help improve the understanding of potential benefits and consequences of genetic testing.

Rationale Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. Objectives To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. Methods Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. Results A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. Conclusions Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. Clinical Trial Registration This study was registered with clinicaltrials.gov (NCT NCT02810327).

Figure. Cardiac imaging and histology for the proband. A, Transthoracic echocardiogram apical and short axis images showing dilated cardiomyopathy (DCM) and increased trabeculation. B, Cardiac magnetic resonance imaging detailing DCM. C, Immunostaining for PLEKHM2: Hoechst (Blue), nuclei. MF20 (Green), myosin heavy chain. PLEKHM2 (Red). Top row: Nuclei (blue) and PLEKHM2 (red) staining. Middle row: nuclei (blue) and cardiomyocytes (green). Bottom row: all 3 stains. The deceased patient has profound reduction of PLEKHM2 staining and hypertrophic myocytes compared with an autopsy control heart.