Homozygosity by descent of a 3Mb chromosome 17 haplotype causes coinheritance of Glanzmann thrombasthenia and primary ciliary dyskinesia

To the editor:

Glanzmann thromboasthenia (GT) is an autosomal recessively inherited bleeding diathesis, and mutations within the genes (ITGA2B and ITGB3) that code for subunits οφ τηε αIIbβ3 integrin have been shown to be responsible for this disorder.¹ 

The GT clinical phenotype can be modulated by a series of factors, acquired as well as inherited.² 

We now report the coinheritance in 2 siblings of GT and primary ciliary dyskinesia (PCD). A 5-generation family history excluded consanguinity. Approval was obtained from the Ospedali Riuniti (Foggia, Italy) Institutional Review Board for these studies. Written informed consent was obtained from the parents in accordance with the Declaration of Helsinki.

The patients were a 9-year-old boy and his 6-year-old brother (Figure 1) who had mucocutaneous bleeding diathesis soon after birth. A diagnosis of GT was confirmed by complete platelet failure to aggregate in response to adenosine 5-diphosphate, epinephrine, collagen, and thrombin and lack of the αIIbβ3 platelet receptor in flow cytometry studies. In both patients, the presence of an opposite position of the internal organs (heart, stomach, spleen, liver, and gallbladder) and bronchiectasis allow for the diagnosis of PCD. In both of these patients, an atrial septal defect, a patent foramen ovale, and an ostium secundum (in the older and in the younger boy, respectively), was observed. In addition, sinus disease with recurrent infections gave rise to recurrent epistaxis, which needed the combined use of recombinant activated factor VII and antifibrinolytics, because of refractoriness to platelet transfusion due to the appearance of antibodies against platelet antigens. Both parents and the 14-year-old sister were asymptomatic.

Sequencing of ITGA2B and ITGB3 genes revealed the presence of a novel homozygous nonsense mutation within the ITGB3 gene (p.W264X, c.G33289A). Both parents were heterozygous, whereas the sister did not carry the mutation.

Clinical and instrumental information indicated the cosegregation of both diseases and suggested the contemporary inheritance of mutated alleles of different genes, raising the possibility of their linked germinal transmission. Usually, because of crossing over, genes follow the expected inheritance patterns predicted by Mendel's Theory of Independent Assortment, and their probability to be separated across generations depends on how far genes are.

PCD is inherited in an autosomal recessive manner and shows high locus heterogeneity, ∼20 genes being known to be associated with the disease.^3-10  One of them, CCDC103, is located in a 3Mb segment on the chromosome 17q, between the ITGA2B and ITGB3 genes. Thus, we explored whether the clinical phenotype observed in the family investigated might be ascribed to the inheritance of a chromosome 17q haplotype. In both patients, sequencing of the CCDC103 gene showed a homozygous missense mutation, p.H154P (c.A2826C), previously reported in families of Pakistan and German origin.⁷  Both parents and grandmothers were heterozygous, whereas the sister did not carry the mutation. To further confirm the pathogenetic role of a chromosome 17q haplotype inheritance, we analyzed informative gene polymorphisms. All alleles cosegregate (Figure 1), providing evidence of the existence of a 3Mb chromosome 17q haplotype, which carries both the ITGB3 p.W264X and the CCDC103 p.H154P gene mutation. The presence of an inherited haplotype and the absence of self-reported consanguinity strongly suggest a common ancestor and a founder effect of a rare haplotype.

To our knowledge, this paper is the first to describe coinheritance of GT with PCD, a hereditary disease that affects GT clinical phenotype by modulating bleeding risk because of the presence of sinusitis, bronchiectasis, and malformations needing surgical approaches, as atrial septal defects.