To the Editor:

I appreciate the opportunity to comment on the thoughtful letter by Drs. Saul and Moeschler in response to my recent editorial in the New England Journal of Medicine on new, recurrent microdeletion disorders identified by cytogenetic array technologies (aCGH, SNP arrays, beadchips).1 I was trying to make two main points related to the discovery of several new microdeletion disorders in the last couple of years based on these powerful new technologies. First, in contrast to some suggestions, a “genotype-first” approach to syndrome identification is not new but was in fact the basis of the description of the first human microdeletion disorders, cri du chat and Wolf-Hirschhorn syndromes. Second, I wanted to remind readers that incomplete penetrance and variable expressivity are well documented in cytogenetic disorders (e.g., del 22q11 syndrome associated with DiGeorge syndrome, velocardiofacial syndrome, autism, and schizophrenia). Some authors and readers have the misconception that the incomplete penetrance and variable clinical presentations of the recently described microdeletions (e.g., del 1q21, del 16p11) represent new phenomena and somehow challenge our notions of causality for de novo deletions and their pathogenic phenotypic effects.

In a brief closing paragraph, I expanded my comments from the scientific implications of these new microdeletion disorders to practical clinical implications and suggested that clinicians too could utilize a “genotype-first” approach to evaluation of children with developmental delay with cytogenetic array testing. Drs. Saul and Moeschler correctly pointed out that my general comments (limited by space constraints in the editorial) could be misinterpreted as a recommendation to primary care pediatricians to forgo referrals to specialists such as developmental pediatricians, pediatric neurologists, and pediatric geneticists, which may uncover specific diagnoses or guide other appropriate medical evaluations and genetic testing.

Although I agree with Drs. Saul and Moeschler that the optimal strategy for evaluation of unexplained developmental delay, mental retardation, or autism is referral to a medical geneticist followed by appropriate laboratory testing, there is a critical shortage of medical geneticists in the United States2,3 and wait-times for genetics clinic appointments can often be several months up to 6 months or more. Cytogenetic array testing is now widely available in many laboratories in the United States, with turn-around times of approximately 2–3 weeks and 15–20% yields for identification of clinically significant abnormalities that end the family's “diagnostic odyssey” and allow specific genetic counseling regarding etiology, recurrence risks, and in some cases, useful prognostic information. In some genetics clinics, including our own, clinicians often recommend cytogenetic array testing before their first visit because a high proportion of patients will need such testing anyway. Additional studies are needed to address both the cost-effectiveness and accessibility of optimal medical genetics evaluation and genetic testing in our current situation of workforce shortages in medical genetics.