NEW_LIVES: Genomic… Human Genetics

Subproject 4: Human Genetics

Genetic Polyclinic, Heidelberg University Hospital

Sequencing and selection criteria for target genes

Genome sequencing, i.e. the examination of all sections of the human genome, is now offered as a diagnostic test for symptomatic adults and children. It is used to diagnose rare hereditary diseases in particular and is increasingly important for planning medical care and therapy. In addition, genome sequencing - and thus genomic newborn screening (gNBS) - is in principle also technically feasible in healthy newborns. However, there currently is no consensus on which genes or diseases should be included in a gNBS program.

In the human genetics subproject, we would like to develop criteria for the selection of genes, focusing particularly on the certainty of genetically based prediction. Factors such as sensitivity, validity of gene-disease association, and penetrance (probability that a person with a disease-relevant variant will actually develop the disease) will play an important role. We will also contribute technical and methodological aspects to the discussion of whether longer-term genetic data storage should be recommended in order to enable usage of this data in the future, or whether data obtained from gNBS should be discarded after the screening is completed, e.g., for privacy reasons, which would necessitate resequencing if genetic information is needed again at a later time. 

Medical benefit - Personal benefit

The availability of a recognized treatment has been a prerequisite for the inclusion of diseases in biochemical NBS since the 1968 publication of the Wilson and Jungner criteria. Yet, in the genomic data set, we can also identify information about conditions we currently are unable to treat, such as hereditary forms of mental disability. Such knowledge could be of great personal benefit for the parents' life planning and further family planning. Studies indicate that, for families, the certainty of a genetic prediction is often more important than the medical actionability of the condition. To the extent that the occurrence of a serious disease can be predicted with a high degree of certainty, optional reporting of findings could be offered as part of a gNBS program even if no treatment is available. This is contrary to the Genetic Diagnostics Act in its current form: According to §16, genetic screening is only permitted if the target disease is "preventable or treatable (...) or (...) can be prevented." The advantages and disadvantages of communicating medically non-actionable results are to be discussed with the project partners with special regard to the legal situation.

Age-dependent penetrance

In the genomic dataset, we also can identify information about diseases that only manifest in adulthood, e.g. a BRCA1-associated tumor disposition. If such a disposition is known in a family, predictive testing of the children should only be performed after they have reached adulthood. Reasons for this include the child's right not to know, possible psychological disadvantages resulting from such knowledge, and considerations of insurance law.

Nevertheless, if such a disposition is detected in the genomic screening process, it may not yet be known in the family. And if this finding is not being communicated then, this potentially life-saving information may be lost to the family. Such knowledge of tumor dispositions could be of immediate medical relevance to parents, for example in that there are established screening options for affected women. For diseases with high penetrance and treatment or screening options, optional reporting of findings could be offered as part of a gNBS program even if the disease does not occur until adulthood. The advantages and disadvantages are to be discussed with the project partners, taking into account the preferences of families and patient groups.


Prof. Dr. Christian Schaaf

Prof. Christian Schaaf, MD, is medical director and chair of the Institute of Human Genetics at Heidelberg University. He is a specialist in human genetics and focuses on the genetic causes of rare diseases. His work has led to the discovery of several new disease genes, and three diseases have been named after him: Schaaf-Yang syndrome, Bosch-Boonstra-Schaaf optic atrophy syndrome and Marbach-Schaaf syndrome. Prof. Schaaf's work has been honored with numerous awards, including the William K. Bowes Award for Medical Genetics from Harvard Medical School, the Seldin-Smith Award for Pioneering Research from the American Society for Clinical Investigation, and the Wilhelm Vaillant Prize.

Heiko Brennenstuhl, MD, is a physician and scientist at the Institute of Human Genetics at the University of Heidelberg. He is a specialist in pediatric and adolescent medicine and is conducting research on the technical implementation of genomic newborn screening. Previously, he was responsible in the Section of Neuropediatrics and Metabolic Medicine for the establishment of a cellular 3D model for the study of neurotransmitter disorders and for the validation of a biochemical marker for AADC deficiency in newborn screening. During his clinical training, Mr. Brennenstuhl completed part-time studies in "Leadership and Management in Healthcare" and obtained the qualification of Master of Business Administration.