My Most Instructive/Informative Patient

Treasure the Exception

Comment by Dr Elaine Zackai.

I have come across two instances that were particularly informative in working with the patients with 22q11.2 deletion. The first was a boy that we saw early on when we were just learning about the 22q11.2 deletion. He had no syndrome diagnoses but the hematologist that followed him for his severe nose bleeds asked me to see him when he was sitting outside the OR waiting to have the inner lining of his nose cauterized. The hematologist had noted that he had had a heart defect (VSD) and some learning differences and 2/3 syndactyly of the toes. I examined him as best I could on his mother's lap and noted overfolded helices of the ears. Although we had not seen a bleeding disorder at that time associated with the 22q11.2 deletion nor had we seen 2/3 toe syndactyly, the presence of the overfolded helices and the VSD prompted me to test the child for the deletion, which was present.

At this same time the hematologist explained the bleeding by diagnosing him with a rare platelet disorder called Bernard-Soulier, an autosomal recessive disorder first described in 1948 characterized by prolonged bleeding times, thrombocytopenia, and large platelets. It was at this time that researchers were localizing the gene for this problem. We got together with these researchers and it turned out that the gene was located in the 22q11.2 region. Thus, the child was deleted for this gene in the 22q region and was found to have a mutation in the gene on the other chromosome 22. This is an example of the deletion unmasking a recessive disorder and explains why this child had the rare exceptional finding of the platelet disorder.


- Budarf ML et al. Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2. Hum Mol Genet 4(4):763-766, 1995. Pubmed Link

- Ludlow LB et al. Identification of a mutation in the GATA binding site of the platelet glycoprotein Ib-beta promoter resulting in the Bernard-Soulier syndrome. J Biol Chem 271(36):22076-22080, 1996. Pubmed Link

There was a similar phenomenon that explained two other patients who had the 22q11.2 deletion but who also had some findings that were very unusual for the majority of the patients. The two boys (separate families) had polymicrogyria and, in addition, had severe findings of keratoderma on their palms and soles. Whole exome sequencing revealed that they had a mutation in a newly described gene SNAP29 which mapped to 22q11.2. This gene was implicated in an autosomal recessive syndrome called CEDNIK which stands for Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma. Therefore, each patient was missing this gene on the chromosome with the 22q11.2 deletion and was found to have a mutation in this gene on the other non-deleted chromosome. Once again this is an example of the deletion unmasking an autosomal recessive condition and helped us understand why these children had some rare exceptional findings.


- McDonald-McGinn DM, et al. Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J Med Genet 50:80-90, 2013. Pubmed link

Author information:
Dr Elaine Zackai
Clinical Genetics Center
The Children's Hospital of Philadelphia
34th and Civic Center Boulevard
Room 8C05
Philadelphia, PA 19104