Essential Clinical Genetics for LEND and UCEDD Programs
Case 2
Asher and the Serendipity of a Family History
As the pre-doctoral audiology LEND trainee you are now shadowing a geneticist, genetic counselor, and metabolic dietician in the Genetics Clinic at Starbright Children’s Hospital. They are all LEND faculty in your program. The first patient in clinic is Asher, a 5-day-old newborn with an abnormal newborn screen for C5-OH. C5-OH is a metabolite that is elevated in a variety of rare but serious metabolic disorders. Before seeing the patient they discuss the disorders that can cause an elevation in this metabolite and the follow up testing that is warranted.
In your small group, discuss your answers to the following questions.
1. Which of the following websites provides a brief information sheet on what to communicate to the family of the patient regarding the abnormal newborn screen results and an algorithm on the basic steps required to determine the final diagnosis in the infant?
A. American College of Medical Genetics and Genomics ACT sheets
B. GeneTests.org
C. National Newborn Screening and Genetics Resource Center website
D. OMIM (Online Mendelian Inheritance in Man)
Based on the history and physical examination, the infant is healthy and eats well. According to the algorithm provided at the appropriate website above, the genetics nurse practitioners orders the following laboratory tests in the infant and his mother: basic metabolic panel, ammonium level, urine organic acids and repeat plasma acylcarnitine profile. The results are all normal in both individuals, and this rules out a metabolic disease in Asher.
Four years later the patient is referred back to genetics for short stature and a history of cryptorchidism (undescended testes). He has no other dysmorphic features (difference in body structures that can be suggestive of a genetic condition). However, the family history that was obtained by the genetic counselor in clinic is documented in the pedigree below (patient is denoted by arrow).
The geneticist and genetic counselor agree that this history is strongly suggestive of Noonan syndrome, a genetic condition that is associated with short stature, congenital heart disease, cognitive disabilities like a learning disability or intellectual disability, characteristic facial features, broad or webbed neck, chest wall deformities, cryptorchidism, and a coagulation disorder. Individuals in the family with features of Noonan syndrome are shaded in black.
2. Noonan syndrome is inherited in an autosomal dominant pattern. What are the features in this pedigree that support an autosomal dominant pattern?
The possibility of Noonan syndrome is mentioned to Asher’s parents. His father states that he recalls another doctor mentioning this condition several years ago, but no one in the family has received genetic testing. Noonan syndrome can be caused by a pathologic mutation in one of seven genes (PTPN11, SOS1, BRAF, KRAS, RAF1, NRAS, and MAP2K1). This is an example of locus heterogeneity (a mutation in one of several genes causes the same clinical presentation). The infant’s parents provide consent to perform genetic testing for Noonan syndrome. They prefer to test Asher since the Asher’s father does not currently have medical insurance, but Asher does through the State Medicaid program.
3. Which of the following websites provides a review of Noonan syndrome and a list of laboratories that will perform genetic testing for this condition?
A. American College of Medical Genetics and Genomics ACT sheets
B. GeneDx website
C. GeneTests.org
D. OMIM (Online Mendelian Inheritance in Man)
4. In individuals suspected of having Noonan syndrome, molecular testing (gene sequencing) of all seven genes is NORMAL in up to 25% of affected individuals? Why?
Sequential molecular genetic testing in Asher identifies a pathologic mutation in PTPN11. This genetic test result confirms that he has Noonan syndrome. Targeted mutation analysis identifies the same mutation in Asher’s father, sister, uncle and grandmother.
The mutation identified in Asher is associated with hypertrophic cardiomyopathy, a progressive thickening of the heart muscle that can occur as a baby gets older and is life-threatening. This mutation is NOT associated with juvenile myelomonocytic leukemia, a cancer that has a higher incidence in some forms of Noonan syndrome.
5. Each affected family member has the same pathologic mutation, but the clinical presentation is different. This is an example of variable expressivity. Why are their clinical presentations different even though they have the same mutation? How does this impact the counseling about prognosis that is provided to Asher’s parents?
6. Based on the clinical features of Noonan syndrome, what additional studies should Asher have or what referrals should be made?