Severe coagulation factor V deficiency associated with an interstitial deletion of chromosome 1q

Abstract

Severe coagulation factor V deficiency associated with an interstitial deletion of chromosome 1q Severe FV deficiency (Mendelian Inheritance in Man *227400) is a rare coagulation disorder that confers a variable bleeding risk, with a prevalence in the general population of approximately one in 1 000 000. The disorder can be further classified as either type I or type II deficiency, with either very low or more moderately reduced FV antigen levels, respectively, both of which are accompanied by reduced procoagulant activity [2][3][4]. Spanning more than 80 kb, the F5 gene is comprised of 25 exons and maps to chromosome 1q23 [5]. Genetic mutations underlying a FV-deficient hemorrhagic diathesis have been described in a limited number of cases and display considerable allelic heterogeneity. Most of the described cases have been due to point mutations in F5 [1,6].Here, we report a novel molecular etiology for FV deficiency in a 15-year-old girl with psychomotor delay, anatomic central nervous system abnormalities, and a solitary left kidney -all features consistent with a congenital 1q deletion syndromewho was found to have severely reduced plasma FV activity during a routine preoperative laboratory evaluation prior to an elective spinal stabilization surgery.The proband, a 15-year-old girl, underwent medical assessment prior to corrective surgery for progressive spinal scoliosis. According to her mother, the girl had experienced no previous abnormal bleeding tendencies. Preoperative testing revealed a mildly prolonged prothrombin time (13.2 s; normal 8.4-12 s; her International Normalized Ratio 1.3) and activated partial thromboplastin time (38 s; normal 21-33 s). She had undergone several minor surgical procedures in the past including placement of tympanostomy tubes and the insertion of a gastrostomy tube, which occurred without significant bleeding. Family members were also clinically unaffected. The patient and her mother consented to further investigations of her condition, in the context of a protocol approved by the Institutional Review Board of Mayo Clinic.Routine plasma-mixing studies and coagulation factor activity assays were performed in the Mayo Clinic Special Coagulation Laboratory. Factor V procoagulant activity assays were performed using FV-deficient plasma (Cryocheck, Precision Biologic Inc., Dartmouth, Nova Scotia, Canada) dropped onto microscope slides and checked by phase contrast microscopy to verify appropriate cellularity. Samples were then subjected to standard fluorescent in-situ hybridization (FISH) pretreatment and fluorescence microscopy methods using a probe covering the FV gene and the more telomeric HPC1 gene as a control.After isolation of genomic DNA from the patient with a resin-based DNA extraction kit, amplification of 25 FV exons was achieved by the polymerase chain reaction (PCR) using paired intronic primers. All PCR primers and conditions are available at http://www.stanford.edu/~zehnder. Products generated by PCR were sequenced using automated fluorescent dye-chemistry m...

Molecular characterization of a patient with an interstitial 1q deletion [del(1)(q24.1q25.3)] and distinctive skeletal abnormalities

“…While many of these cases have a significant overlap in phenotypic findings, the regions of deletion are fairly large and in many cases have not been precisely mapped at the molecular level. Until now, 21 cases including ours have been described with 1q22q25 deletion [Schwanitz et al, 1977; DePablo et al, 1980; Schinzel and Schmid, 1980; Moghe et al, 1981; Higgins et al, 1982; Martin and Simpson, 1982; Taysi et al, 1982; Silengo et al, 1984; Beemer et al, 1985; Zaletaev et al, 1987; Franco et al, 1991; Leichtman et al, 1993; Lo et al, 1993; Takano et al, 1997; Melis et al, 1998; Pallotta et al, 2001; Schwemmle et al, 2006; Caudill et al, 2007]. There have been 11 published cases with 1q25q32 deletions [Crandall and Falk, 1974; Turleau et al, 1974; Garver et al, 1976; Koivisto et al, 1976; Pan et al, 1977; Steinback et al, 1984; Faugeras and Barthe, 1985; Hamano et al, 1987; Scarbrough et al, 1988; Hoglund et al, 2003; Maggio et al, 2003].…”

Advances in understanding the bleeding diathesis in factor V deficiency

“…In contrast, truly null FV defects, such as large F5 deletions or chromosomal rearrangements involving the F5 gene, would be incompatible with life if present in the homozygous or doubly heterozygous state, as suggested by the fact that gross F5 gene deletions have never been found in FV‐deficient patients. A complete deletion of one F5 allele has been recently reported in a patient who also carried a missense mutation (Ser 234 →Trp) on the other F5 allele, resulting in 9% residual FV activity and (remarkably) no history of bleeding (Caudill et al , 2007).…”

Factor V deficiency: a concise review

“…Clinically important nonsense, frameshift, missense, and splice‐site mutations in the FV gene have all been described. Recently a patient has been described with a FV level of 9% who has a complete deletion of one FV allele in association with a 1q deletion on one chromosome combined with a point mutation in the other FV allele [18]. In light of the severe phenotype of the FV knockout mice, which die either in utero at embryonic day 9–10 or within a few hours of birth from massive haemorrhage [19], the lack of patients with complete gene deletions has led to the hypothesis that complete FV deficiency is incompatible with life [4].…”