Cases from the Outcomes Workgroup

1. Cases from the Outcomes Workgroup Maureen Smith Alanna Rahm Cindy Prows

2. Northwestern Participant • 59 year old male • No indication for genetic testing • Contacted the study himself to participate • Wife also participated • Heard about the study through word of mouth • PCP and ENT at Northwestern Medicine • Study results: 2 CFTR heterozygous gene mutations, F508del (pathogenic)/R117H/7T (likely pathogenic) • Results were returned by a genetic counselor over the phone • Participant reported the following personal medical history: • Congenital absence of the vas deferens (CAVD) • Chronic sinusitis that frequently tests positive for pseudomonas aeruginosa, history of two prior sinus surgeries • Digestive issues, including a dairy allergy that aggravates his sinuses, foul smelling stools, increased flatulence, and a lean BMI despite a large appetite • Reportedly very susceptible to illness

3. Northwestern Participant: Post Results • Participant contacted PCP and ENT regarding results; reported he was happy to get explanation of infertility and expressed anxiety regarding future pancreatic and infectious implications. • Changed urologist to see physician at Northwestern Medicine (all NM physicians) • Genetic Counselor referred participant to Adult CF clinic (located at children’s hospital), full workup including the following findings: • Sweat chloride; Left arm: 38 mmol/L, Right arm: 36 mmol/L (30-59 intermediate range) • Lung imaging; revealed mild air trapping, predominantly in the lower lobes without bronchiectasis and several groundglass nodules that could be infectious and/or inflammatory. Recommended follow-up noncontrast CT chest in 3-6 months. • Chest x-ray; no acute cardiopulmonary process, some mild bronchial wall thickening seen in the lower lobes bilaterally which suggests reactive airway disease • Chest CT; revealed secondary findings in thyroid (calcifications) and kidney (hypodense lesion). Recommended ultrasound for each and both found to be benign. Repeat thyroid US in one year. • Vitamin-D levels low (pulmonology)- 13 (ref range 30-100); after intervention levels were retested and normal. . • IgE levels elevated: 425 kU/L (ref range: <115) • Therapies initiated: • Ergocalciferol (Vitamin D2) for treatment of Vitamin D deficiency which can be related to pancreatic insufficiency; • Kalydeco, a proton-pump inhibitor specific to his R117H/7T variant; Treatment with Kalydeco impacted dermatology and urology care requiring him to switch from ketoconazole shampoo to ciclopirox shampoo and discontinue Cialis respectively. • Albuterol and tobramycin via a nebulizer. • Overwhelmed by new medications and chose to discontinue his Clomid. CF clinic records kept at Children’s hospital-we do not have direct access; all f/u second hand from PCP/ENT office visit notes, phone calls and other communications

4. Geisinger Participant • 61 year old Female • MyCode participant. Consented August 8, 2014 in Internal Med. • Multiple comorbidities: DM type 2 with diabetic peripheral neuropathy, stage 3 chronic kidney disease ,proliferative diabetic retinopathy with macular edema, bilateral, hypothyroid, former smoker, angina pectoris, hypertensive heart disease, peripheral artery disease, obesity, anemia. • June 2009 right breast lumpectomy due to grade 3 invasive ductal carcinoma with chemo and radiation therapy. • Amputation of right foot June 5, 2017 with complications including an ischemic stroke. • Result: LDLR. ROR on August 30, 2017 while patient was in care facility recovering from amputation. • ROR Call: Patient stated she was in nursing home for rehabilitation following amputation surgery of right foot, stated she had stroke after surgery and is wondering if can be related to result. Scheduled appointment to see GC and requested result info packet sent to rehab facility where recovering • ROR appointment: no-show, patient called to say was in ambulance will call back when home. Patient eventually rescheduled and discussed result with GC

5. Geisinger Participant – post result • Further amputation complications led to another stroke 1 month post ROR. • Amputation of left foot 4 months post ROR. Additional CAD diagnosis post ROR. • Unable to tolerate statins • Specialist followups including stress test – modified due to double amputation • After 1 year now has breast cancer diagnosis, further amputations of leg. • Concerned for son having similar experiences who “doesn’t take care of himself” – heart attack at 39. she is concerned he has the condition but so far no notes in chart on cascade testing • Patient now residing in nursing home outside of system – no additional records available for review, other than ED visits and some CareEverywhere encounters visible in EPIC.

6. CCHMC Adolescent Cohort: CACNA1A • Enrolled without clinical indication • Adolescent and parent independently and jointly chose to learn all possible results • Family history screen at study visit • Father & sister with migraine, temporary muscle weakness / paralysis • Adolescent’s Result: Het c.6321+1G>A, Intron 44, LP • Risk – episodic ataxia type 2 • Telephone disclosure to mother and adolescent; summary letter with report to family & primary care provider; discrete results entered into EPIC (viewable in MyChart); CCHMC specialists sent staff message alerting them to result placed in EPIC.

7. CCHMC Adolescent Cohort: CACNA1A • 1 month later, evaluated in genetics clinic • Adolescent ROS negative, Medical history negative, cleared for wrestling • Targeted variant testing: Mother, father and younger twin siblings • Mother periodic numbness, falling, word choice issues. Previous neurology evaluations negative • Father: hemiplegic migraines with strenuous exercise when younger • Siblings with migraines (possibly hemiplegic) after strenuous exercise • Sister followed by pediatric neurologist • “I could have avoided spending thousands of dollars on MRIs and EEGs if I had known gene result.” • Requesting neurologist that specializes in CACNA1A related ataxia