Balkan Journal of Medical Genetics

CASE REPORT FOR TWO SIBLINGS CARRYING NEUROFIBROMATOSIS TYPE 1 WITH A RARE NF1: c.5392C>T MUTATION
Sayın Kocakap DB, Gündüz Ö, Özer L, Durak M
*Corresponding Author: Associate Professor Derya B. Sayın Kocakap, Kırıkkale Üniversitesi Tıp Fakültesi Tıbbi Genetik AD, Ankara Yolu 7.km, 71450, Kırıkkale, Turkey. Tel.: +90-318-357-3300/5784. Fax: +90-318-225-2819. E-mail: dsayin@yahoo.com
page: 99

MATERIALS AND METHODS

Case 1. A 21-year-old male patient presented to our dermatology clinic due to presternal papulopustular eruption, consistent with bacterial folliculitis. Dermatological examination revealed multiple café au lait macules along with a few asymptomatic subcutaneous soft papules on his shoulders and deltoid regions. Bilateral inguinal and axillary freckling were also present (Figure 1). Lisch nodules on both irides were seen in his ophthalmological examination. Based upon the presence of axillary and inguinal freckling, café au lait macules, and Lisch nodules, the patient was diagnosed with NF1. Further clinical examination and anamnesis did not reveal any other sign or symptom of NF1. Case 2. After a few weeks, a 24-year-old female patient, the elder sister of the first case, presented at our clinic due to the recent diagnosis of her brother with NF1, although she did not have any specific complaints. Several asymptomatic light brown patches, café au lait spots, were visible on her abdomen, in the right lower quadrant, and on her right flank [Figure 2(a) and 2(b)]. The flexor surfaces of her right arm and forearm were covered with flesh-colored, painless non indurated continuous plaques [Figure 2(a)]. Her left arm was also hypertrichotic [Figure 2(c)]. A biopsy from the plaques revealed prominent immunohistochemical staining with S100, indicating a neural sheath tumor. Further opthalmological, neurological and orthopedic examinations revealed no additional pathology. The family medical history showed similar skin lesions in their paternal grandfather, father, uncle, aunt, cousins and brother. The pedigree is shown in Figure 3. Mutation Analysis. Genomic DNA was isolated from peripheral blood samples using the QIAamp DNA Blood Mini kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer’s instructions. Next-generation sequencing (NGS) was performed on a MiSeq (Illumina Inc., San Diego, CA, USA), following the manufacturer’s instructions for the NF1 gene. The procedure for the preparation of libraries was performed according to the manufacturer’s instructions. The hg19 (GRCh37) reference sequence was used as a reference for identifying genetic variants. The variant call formats (VCF) files were analyzed by Variant studio (Illumina Inc.) and Geneticist Assistant (SoftGenetics, State College, PA, USA) software program. The sensitivity of this test was determined as 99.0% for 5.0% single nucleotide polymorphism (SNP) allele fraction rate with 1000× coverage. The specificity of this test was determined as 99.0% for 0.5% SNP allele fraction rate with 1000× coverage. All identified variants are evaluated with respect to their pathogenicity and causality and categorized into classes according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines [6]. Heterozygous class 1 c.5392C>T, p.Gln 1798Ter mutation in exon 38 of the NF1 gene has been detected with a mutation surveyor program. Detected variants were also analyzed and confirmed by Sanger sequencing (Figure 4) according to the manufacturer’s protocols. Briefly, the amplicons were analyzed by direct sequencing with ABI PRISM® 3500 (Life Technologies, Waltham, MA, USA). Analysis of sequence results was done by the Mutation Surveyor program (SoftGenetics). The primer sequences and polymerase chain reaction (PCR) conditions will be provided by the corresponding author upon request.

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