GENETIC ANALYSES OF THE NF1 GENE IN TURKISH NEUROFIBROMATOSIS TYPE I PATIENTS AND DEFINITION OF THREE NOVEL VARIANTS
Ulusal SD1,*, Gürkan H1, Atlı E1, Özal SA2, Çiftdemir M3, Tozkır H1, Karal Y4, Güçlü H2, Eker D1, Görker I5
*Corresponding Author: Dr. Selma D. Ulusal, Department of Medical Genetics, Trakya University Faculty of Medicine, D100, Edirne, Turkey. Tel: +90-284-235-7642/2330. Fax: +90-284-235-7652. E-mail: selmaulusal@trakya.edu.tr
page: 13

RESULTS

Pathogenic Variant Distribution. In total, a large gene deletion (patient #17) and 15 different pathogenic variants were determined. Truncating pathogenic variants either due to small deletions (3/18) or point mutations (4/18) had the highest frequency followed by splice site mutations (6/18). Missense mutations (2/18), in-frame deletion (1/18) and a large gene deletion (1/18) were also defined in the studied population with relatively rare frequencies (Table 1). Three of the pathogenic variants were novel (patients #6, #8, #12). One of the novel pathogenic variations, c.3230_3230delT, predicted to cause p.(Ser1078Hisfs*3), was colocated with a previous pathogenic variation reported in LOVD (patient data #0060922). This previous pathogenic variation was a duplication of Timin, whereas in our patient it was a deletion of the first Timin base of codon 1078 (NM_000267). The second novel pathogenic variant, c.4802delT, p.(Leu1601Cysfs*2) in the clinically affected father of the index patient. Absence of this variant in the unaffected family members and in the Exac database supported the pathogenic features of this frameshift variant. A broken tibia because of a severe pseudoarthrosis (Figure 1) was determined in this patient who had inherited this novel pathogenic variation from his father who had cafeau-lait spots and neurofibromas all over his body but he had no tibial pseudoarthrosis in his medical history. Another novel variation was c.5630 T>A, predicted to cause a truncated protein [p.(Leu 1877*)]. This novel pathogenic variation was inherited from the father who have cafe-aulait macules. Distribution of pathogenic variants across the domains is shown in Figure 2. Forty percent of pathogenic variants were in the C-terminal region (Figure 2), whereas none of the pathogenic variants found were localized inside the coding region of tubulin binding domain. We did not define any pathogenic variation or deletion in seven out of 24 index patients who were referred to our center suspected of having NF1. Five out of seven of these mutation-negative patients did not meet the NIH diagnostic criteria (Table 2), whereas in the mutation-positive patient group, 13 out of 17 patients met these criteria. We performed physical examinations on the parents of 10 out of 24 patients (patients #1, #5, #6, #8, #10, #15, #16, #17, #20, #22). Five out of 10 of these index cases had at least one clinically affected parent (patients #1, #5, #6, #8, #16), whereas the parents of the remaining five cases were found to be normal after a detailed clinical examination (#15, #16, #17, #20, #22). Familial genetic analysis was available for six out of 17 pathogenic variation-positive patients. Three out of six (50.0%) of these pathogenic variations (c.6756+1G>T, c.7096_7101del and the entire gene deletion) were de novo compatible with parents who did not have clinical findings of NF1. Patient #15, who has a c.7096_7101del [p.(Asn2366_ Phe2367del)] pathogenic variation, was shown to carry this variation de novo but she has transmitted this pathogenic variation to her son who has clinical findings of NF1 (Table 3). The c.6756+1G>T variation has been found in a patient with a plexiform neurofibroma and cafe-au-lait spots. Parents have been found to be apparently normal after detailed physical examination compatible with de novo mutation result in the patient. The entire gene deletion was determined in patient #17 and was shown to be a de novo pathogenic variation by segregation analysis in the parents by MLPA (Table 3).



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