Inherited Giant Platelet Disorder, Kashmiri Thrombocytopenia, a Common Syndrome Found in Srinagar, India
Authors: Lorenzo Felipe R , Tashi Tsewang , Koul Parvaiz , Camp Nicola J , Thiagarajan Perumal , Prchal Josef T. 
Published: October 2019

Abstract
The causative genetic mutations of inherited giant platelet disorders (IGPD) encompass genes coding for the platelet glycoprotein Ib-IX complex (Bernard Soulier syndrome and its variants), myosin heavy chain 9 (MYH9 gene mutated in May-Hegglin anomaly and other IGPDs), GATA-01 (GATA-related thrombocytopenia), TUBB-1, ITGA2, ITGAB3, FLNA and some others. IGPDs are frequently associated with other disorders including renal disease, sensorineural deafness, and leukocyte inclusion bodies. Most are accompanied with variable degrees of bleeding diathesis, while others, like TUBB1 IGPD, do not have any bleeding manifestations. Harris platelet syndrome (HPS), previously called asymptomatic constitutional macrothrombocytopenia, is an autosomal dominant disorder characterized by low-normal to severe thrombocytopenia IGPD and absence of bleeding. HPS has also been observed in healthy blood donors from the northeastern part of India (Bengal) and some areas of Bangladesh, Bhutan and Nepal.
We describe a high prevalence of an autosomal dominantly inherited form of IGPD with mild to severe thrombocytopenia in the Muslim population in Kashmir Valley in the northern Indian subcontinent. 830 voluntary, healthy, male blood donors from Kashmir Valley were included in the study. They were aged 15-55 years (median 31 years) and underwent ancillary screening as follows; CBC, peripheral smear, HBV, HCV, HIV, ANA and Anti-H pylori antibodies. 15% of the donors had thrombocytopenia (mean platelet count 109.6 compared to 189.9 in controls; p=<0.0001). No differences were noted in age between the 2 groups. The mean platelet volume (MPV) in thrombocytopenic subjects was higher (12.53 + 0.78 vs 9.52 + 1.03 fl). The red cell distribution width (RDW) in thrombocytopenic subjects was higher than in those with normal counts (15.6 + 1.61 Vs 13. 22 + 1.36, p=<0.001). Hematocrit and other red cell indices were not different in the 2 groups. None of the participants had a history of bleeding, renal disease, sensorineural deafness, or leukocyte inclusion bodies. Peripheral blood platelet morphology revealed large platelets in all subjects. In a pilot study of 7 families, Kashmiri thrombocytopenia was compatible with autosomal dominant inheritance affecting both genders. The congenital nature of Kashmiri thrombocytopenia was demonstrated by analyses of 34 consecutive neonates born in Sher-i-Kashmir Institute Hospital; among 20 girls and 19 boys, we found 18% (2 male and 5 female) to have low platelet count, the mean platelet count of the affected group when compared to unaffected group were 102.6 vs 234 (p=<0.001) respectively.
We then searched for a causative mutation using the following approaches. We sequenced the MYH9 gene and no mutation was found. We then employed SNP array analyses using Shared Genome Segment (SGS) and Whole Genome Association Study (WGAS). We were able to exclude all previously reported IGPD-causing genes. SGS that overlapped with WGAS narrowed the target into 3 chromosome regions in Chr. 5 (rs6872531-rs100072476), Chr. 9 (rs11999541-rs12682912) and Chr. 10 (rs11013452-rs7083349). The performed SNP analyses included large genomic segments as candidates for a Kashmiri thrombocytopenia-causative gene. To further narrow down the cause of this disorder, we recruited 3 TRIO families (an affected parent and a child) for stronger linkage analysis and next-generation sequencing to continue the search for the cause of the Kashmiri thrombocytopenia.

Disclosures
No relevant conflicts of interest to declare.