第47回大阪小児先進医療研究会セミナー Whole exome sequencing: novel causes of short and tall stature, and big tes;cles 演者 座長 日時 Jan-‐Maarten Wit, MD, PhD, emeritus professor of pediatrics, Dept of Pediatrics, Leiden University Medical Center, Leiden The Netherlands 大阪大学大学院医学系研究科 小児科学 教授 大薗 恵一 先生 平成28年 5月27日（金） 18:00－19:00 臨床研究棟 3階セミナー室 大阪大学 吹田キャンパス 場所 Abstract The convenJonal approach of the clinician confronted with a paJent with a congenital syndrome is to take a thorough medical history (including a full family history and full pedigree), perform a detailed physical exam, request further invesJgaJons, construct a differenJal diagnosis, and test for candidate genes. At present, one can choose (for well selected cases) to perform whole genome microarray (SNP array) and whole exome sequencing (WES). In general, DNA should be collected from the index case and parents (“trio”), and (if available) from (un)affected sibs; DNA from unaffected relaJves is o\en important for selecJng potenJally pathogenic variants. If a potenJally pathogenic gene variant is found, tesJng other relaJves is important (to check for cosegregaJon with phenotype). In this presentaJon five examples will be discussed in whom WES led to interesJng and unexpected findings. First, in a short girl (height SDS -‐3.3), born with a normal birth weight and length, with a normal si_ng height/height raJo and relaJvely large head circumference (-‐0.5 SDS), and with a short mother and maternal grandmother, WES showed a heterozygous missense mutaJon in FGFR3, close to hypochondroplasia mutaJon p.Asn540Lys, segregaJng with short stature. Second, two brothers presented with short stature (-‐4.7 and -‐3.4 SDS) and a normal si_ng height/height raJo. Based on scoliosis, wide thorax, platyspondyly and epimetaphyseal changes at skeletal survey the diagnosis Spondylo-‐EpiMetaphyseal Dysplasia (SEMD) was made. WES revealed compound heterozygous mutaJon in PAPSS2, which encodes the enzyme generaJng PAPS, the universal sulfate donor. Third, in a 221 cm tall adult giant without skeletal deformiJes we found an acJvaJng mutaJon in NPR2, the receptor for CNP. Fourth, two siblings with extreme microcephalic primordial dwarfism and hypogonadism werd found to have a homozygous mutaJon in XRCC4, which plays a role in nonhomologous end-‐joining. Fi\h, we discovered a novel syndrome in two independent families characterized by central hypothyroidism and macroorchidism, and variable hypoprolacJnemia and GH deficiency, caused by IGSF1 mutaJons. Therea\er, we discovered more than 60 paJents with this syndrome, and I shall discuss the phenotype in some detail. ＜お問い合わせ先＞大阪大学大学院医学系研究科 小児科学講座（担当：窪田 拓生） ※大学院生の受講単位として認定されます（参加費無料） 共催：大阪小児先進医療研究会セミナー JCRファーマ株式会社
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