Demo day: WES in diagnostics of monogenic diseases

Instructions

• In all exercises, the main task is to find the causative variant of the described phenotype. Document how you came up with your conclusion.
• What is the effect of the variant - on the gene and on the protein level? Is the systemic effect of variants in hte gene dominant or recessive? What is the zygosity of the variant? Given the systemic effect, is the variant sufficient to explain the disease? What is the description of the phenotype in OMIM (find Clinical Synopsis).
• What is the next best candidate?
• Which additional laboratory test you would ask for and why?
• WES analyses can be found here. Type "training" in the search window.

• Exercise 1: An athlete with glycogen storage disease

  Individual in this case study is a 28-yr-old woman of Hispanic origin, who presented at the age of 25 years with episodic rhabdomyolysis, postexercise myalgia, and myoglobinuria. Medical history is significant for hypothyroidism, migraine headaches, anxiety, and attention deficit hyperactivity disorder. Family history is negative for similarly affected individuals. She was a competitive cheerleader, g ymnast, and snowboarder from age 13 to age 24 years, but had muscle pain with exertion. At the age of 25 years, during an evening of drinking alcohol and dancing, she developed acute painful leg cramps and swelling as well as pigmenturia. She was admitted to a local hospital with markedly elevated creatine kinase (CK) of 107,000 U/L, which gradually declined over 10 days. Subsequently, he had more than 10 acute episodes of exertion-induced hyper-CKemia (>10,000 U/L). Because of a combination of anxiety about recurrent exercise-induced myalgias and hyper-CKemia as well as inadequately treated hypothyroidism in her late 20s, she became deconditioned, fatigued, and felt subjectively weak with a normal neurological examination. With increased levothyroxine and a mild exercise program, her symptoms improved; however, she reports marked exercise intolerance with activities such as moving the headboard of her bed, which provoked myalgias and CK elevation to 14,000. She also has daily swelling and pain in her lower extremities after minimal exertion, followed by pain and swelling in her upper extremities on subsequent days.

• Exercise 2: A young adult with progressive spastic paraplegia

  A 27-yr-old man, born from consanguineous parents, developed social withdrawal and frequent falls due to progressive lower limb spasticity when he was 4-yr-old. At age of 5, he presented cognitive impairment and astatic seizures. He has been wheelchair-bound since the age of 20. Brain MRI, performed at the age of 16, disclosed thinning of the corpus callosum, especially the genu, T2 hyperintensity, and T1 hypointensity in the forceps minor of the corpus callosum, resembling a milder form of the “ears of the lynx” sign , which raised the suspicion of SPG11. His serum ammonia level, measured at the age of 16, was 86 µmol/L (NR: 11–32 µmol/L). Arginine serum levels were not measured. This patient was treated only with dietary protein restriction since the age of 18 and had no significant improvement after treatment.

• Exercise 3: A woman with late onset ataxia

  This 50-yr-old woman was admitted for a second opinion by her general practitioner. She had no family history of ataxia or other neurological disorders, and no history of migraine or seizures. She was diagnosed with hypothyroidism at age 45 and since then substituted with levothyroxine sodium (Eltroxin) 100 µg daily with no complications. Otherwise, her previous medical history was unremarkable except for a fall from a horse at age 13. She did not have any sequelae from this fall; however, the first time she was riding a horse after the fall, she experienced a short-lasting attack of dizziness. From that time, she experienced episodes of dizziness lasting hours one to two times a month.

  The episodes are initiated by a feeling of distress followed by a feeling of alcohol intoxication, imbalance, slurred speech, and double vision. At a younger age, she also experienced nausea but presently she has more a tinnitus-like feeling of airplane noise from a long distance. The episodes may last from 1 to 5 h. During the last 2 years she has noticed almost daily interictal involuntary muscle movements in her thighs and toes, especially the left-sided lateral toes, waxing and waning, lasting minutes to 2 hours, but not necessarily at the same location or simultaneously. She had no excessive use of caffeine or alcohol.

• Exercise 4: A man with severe dilated cardiomyopathy

  The proband is a 23-yr-old male with familial DCM. He was born to healthy and nonconsanguineous parents. His older brother died at the age of 16 because of a heart transplant rejection, one and a half years after heart transplantation because of heart failure due to DCM of unknown etiology. The proband has another 29-yr-old older brother who is healthy.

  Clinical symptoms in the deceased brother started at the age of 14.5 yr when he was hospitalized because of DCM and heart failure. Before that period, he was otherwise a healthy adolescent with normal toleration of physical activity. Ten days before hospital admission, he was treated because of respiratory infection, after which he started to feel tired, and complained of nonspecific abdominal pain due to organomegaly and cough due to pulmonary edema. Echocardiography revealed dilatation of the left ventricle (LV) and low LV myocardial contractility with a reduction of ejection fraction of LV to 10%–14%. Cardiac magnetic resonance imaging (MRI) revealed extreme dilatation of the left ventricle, reduction of global systolic function to 11%, and areas of diffuse fibrosis of the left ventricle. The right ventricle (RV) showed similar, but less pronounced MRI changes with the reduction of ejection fraction to 19%. Amino-terminal-pro hormone B-type natriuretic peptide (NT-proBNP) was increased to 9324 pg/mL (normal <125 pg/mL). Myocarditis was suspected. After initial medicamentous stabilization (diuretics, digoxin, peripheral vasodilators, and sodium and water intake reduction), he was considered for heart transplantation, which was performed at the age of 14 yr and 10 mo. He was clinically stable 1 yr after transplantation. At the age of 16 yr and 3 mo, he was hospitalized because of progressive cardiac decompensation caused by acute humoral rejection requiring immediate initiation of veno-arterial extracorporal membrane oxygenation. Despite immediate therapy of acute humoral rejection (mycophenolate-mofetil, cyclosporine, plasmapheresis) clinical course was unfavorable and was further complicated by bilateral pneumonia and multiorgan failure, and the patient died after 2 mo at the age of 16 yr and 5 mo.