A Focus on: The Changing Research Agenda of Pediatric Geneticist in the Post-Genomic Era

By Professor Robert P. Erickson 

Image credit: CC0 Public Domain via Pixabay.

Judith Hall has recently dealt with the changing clinical landscape in this era for pediatric geneticists in her essay, “The Computer and the Clinician.” However, the landscape for research efforts is also changing.  With the advent of Next Generation Sequencing (NGS), both Total Exome Sequencing (TES) and Whole Genome Sequencing (WGS), the identification of the genes in which mutations cause even very rare syndromes is rapidly coming to completion.  In most cases, detailed biochemical, gene expression, and developmental studies are well underway (see Erickson and Wynshaw-Boris’s Epstein’s Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, 3rd ed., 2016, for many examples).  The advent of CRISPr technology allowing the rapid substitution of the normal allele with mutant alleles in mice is greatly augmenting such studies. 

One area which will certainly gain more attention is the cause for variable penetrance and expressivity of the genes causing these disorders.  NGS has shown us that some individuals, homozygous or compound heterozygous for well characterized pathogenic mutants, can be non-penetrant for a disorder (Chen R, et al., 2016).  Although it was pointed out years ago (e.g. Erickson, R.P.,1979) that modifying genes would be very important for such variation, NGS provides an opportunity to compare the sequences of many genes between the extremes of penetrance and expression to look for such modifiers.  The ability to manipulate the genome in animal models will allow relatively rapid testing of such potential modifiers.

It is my [our] belief that much more emphasis will be focused on the search for therapies for these disorders in this new era.  Gene therapy is becoming more successful in the treatment of defects of prenatal onset such as Lebers congenital amaurosis (Bennett J, et al, 2016) or retinitis pigmentosa (Beltran WA, 2015.)  Induced pluripotent stem cells can be edited to correct the gene defect and differentiated to cells that might replace damaged cells, e.g. in Duchenne muscular dystrophy (Li HL, et al, 2015). Most gene therapy or stem cell treatments such as these are not useful to patients with altered patterns of development because undoing mistakes made prenatally, especially of brain “wiring”, are difficult/impossible to undue.  Thus, the Pandora’s box of gene editing in the pre-implantation embryo will undoubtedly be opened.

As we approach the era when everybody can/will have TES, and it might become the mode of newborn screening such that it will be available “in the Cloud” from birth (but, presumably, not available to the individual until age 18.) It will not be long until it will be performed by WGS to find the missing 15% of mutations.  With this information, couples will be able to know what recessive mutations they harbor in common.  While the most prudent approach to preventing the birth of an affected child would use prenatal diagnosis of stages from pre-implantation to pre-viability, there may be times when there are multiple genetic disease risks, poor embryos or other situations where gene editing would be sought.

The ability to use CRISPr or TALEN approaches to modify genes has been much improved (Li, et al, 2015), in part because new enzymes of higher specificity are being used (Kleinstiver BP, et al, 2016).  The efficacy and safety are already being studied in human embryos in Great Britain, where such studies have been approved because the experimental embryos must be destroyed when 14 days old, and in China (Kang  X, et al, 2016).  The ethical issues are being much discussed and the American society of Human Genetics is preparing a policy statement on Genome Editing. We are rapidly approaching the kind of world depicted in the sci-fi movie, GATTACA.  Will we use these techniques more ethically than depicted there?


Robert P. Erickson is the Holsclaw Family Professor Emeritus of Human Genetics and Inherited Disease in the Department of Pediatrics at the University of Arizona. Along with Anthony J. Wynshaw-Boris, he is the co-editor of the new edition of Epstein's Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, which is available in print and online.



Erickson, R.P. & Wynshaw-Boris, A.J., 2016. Epstein’s Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, 3rd ed., Oxford University Press.

Chen R, et al, 2016, Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases, Nature Biotech., 14: pp.531-538

Erickson, R.P. ,1979, Birth Defects Orig. Art. Series, XV, 5b, pp. 3-12

Bennett J, et al, 2016, The Lancet, doi:10.1016/S0140-6736(16)30371-3

Beltran WA, 2015, Proc. Nat’l Acad. Sci,USA, doi/10.1073/pnas.150991411

Li HL, et al, 2015, Stem Cell Rept.s, 4:143-154

Kleinstiver BP, et al, 2016, Nature Biotech., doi:10.1038/nbt.3620

Kang  X, et al, 2016 J. Assist. Reprod. and Genet., doi:10.1007/s10815-016-0710-8


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