In medicine, one must think of the possibility of a genetic effect. Familiarity may be indicative, but genetic diseases also occur sporadically. With state-of-the-art high-throughput sequencing, diagnoses can now be made that until recently took a long time or were not possible at all. Genetic diagnostics has importance not only for targeted prevention and family counseling, but also for causal treatment.
Diseases can be genetic. In common multifactorial diseases such as hypertension and diabetes, the genetic effects are usually multiple and only strong in the aggregate, whereas a monogenic disease is based on mutations of only one gene. Monogenic diseases almost all belong to the rare diseases (prevalence <1:2000), which are therefore underestimated in terms of health policy and often do not receive optimal care. However, since there are more than 5000 different rare diseases, the total number of people affected is large and equal to the number of diabetes patients in this country.
Genetic revolution in medicine
Only recently have rare diseases begun to receive the attention they deserve. Genetics is making a decisive contribution with new methods. In addition, strong genetic effects can also be seen in subgroups of common diseases such as familial forms of breast or colorectal cancer. In addition, the medical significance of somatic mutations has come to the fore in recent years, such as in hypertension due to hyperaldosteronism [1] or in subtypes of epilepsy [2]. Epigenetic changes, which do not directly affect the DNA sequence but rather gene regulation, are also becoming increasingly important.
Prominent among the new methods of genetics are genomic analyses (not to be confused with Internet or pharmacy genetic tests). While still relatively expensive, these have been particularly successful in disease detection, analysis of cell-free DNA circulating in the blood – allowing genetic assessment of tissues without biopsying them directly – and single-cell examination of minute biospecimens. With these advances, the medical importance of genetics is rapidly increasing. The following three case studies are intended to illustrate this.
End of a diagnostic odyssey over ten years
One child was already conspicuous since birth with muscle hypotonia and developmental delay. Later, epilepsy and severe scoliosis were added. Multiple and costly investigations over ten years were unsuccessful.
Our genome-wide analysis revealed evidence of de novo deletion of ~50 genes. Since described cases with comparable deletion showed similar symptoms, the diagnosis was made and the patient’s “diagnostic odyssey” could be ended.
New syndrome subtype
A tall girl had suffered two syncope episodes, which worried her parents very much. First-grade AV block and aortic root diameter at the upper normal limit were found, but no clear diagnosis was made. Clinical genetics showed a marfanoid habitus without ocular symptoms but with cleft of the soft palate.
Examination of those genes known to be or potentially causative of the present clinical signs revealed evidence of a TGFB3 neumutation [3]. Since TGFB3 mutations were also described in similar patients shortly thereafter [4], the diagnosis of a new subtype of Loeys-Dietz syndrome (LDS type 5) was confirmed in our patient. This had direct relevance to their clinical care, as LDS patients are prone to severe cardiovascular complications.
Family member initiates genetic workup
The husband of a 46-year-old patient with bilateral renal carcinoma heard that his father-in-law had also already had kidney surgery. While doctors did not think so despite the bilateral nature, he suspected a familial form of renal carcinoma, autosomal dominant Birt-Hogg-Dubé syndrome (BHD), especially since the patient had lung cysts and her father had skin follicles in the head and neck. He contacted us and we were able to detect a FLCN mutation causative for BHD in the patient and her father [5]. This not only provided the correct diagnosis, but also offered targeted genetic workup for the family.
Literature:
- Beuschlein F, et al: Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: 440-444.
- Lim JS, et al: Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21: 395-400.
- Matyas G, et al: De novo mutation of the latency-associated peptide domain of TGFB3 in a patient with overgrowth and Loeys-Dietz syndrome features. Am J Med Genet A 2014; 164A: 2141-2143.
- Bertoli-Avella AM, et al: Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol 2015; 65: 1324-1336.
- Näf E, et al: Birt-Hogg-Dubé syndrome: Novel FLCN frameshift deletion in daughter and father with renal cell carcinomas. Fam Cancer (under review).
HAUSARZT PRAXIS 2015; 10(9): 9
