Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing

被引：36

作者：

Iwama, Kazuhiro ^{[1
,2
]}

Mizuguchi, Takeshi ^{[1
]}

Takeshita, Eri ^{[3
,4
]}

Nakagawa, Eiji ^{[3
]}

Okazaki, Tetsuya ^{[5
]}

Nomura, Yoshiko ^{[6
]}

Iijima, Yoshitaka ^{[7
]}

Kajiura, Ichiro ^{[7
]}

Sugai, Kenji ^{[3
]}

Saito, Takashi ^{[3
]}

Sasaki, Masayuki ^{[3
]}

Yuge, Kotaro ^{[8
]}

Saikusa, Tomoko ^{[8
]}

Okamoto, Nobuhiko ^{[9
]}

Takahashi, Satoru ^{[10
]}

Amamoto, Masano ^{[11
]}

Tomita, Ichiro ^{[11
]}

Kumada, Satoko ^{[12
]}

Anzai, Yuki ^{[13
]}

Hoshino, Kyoko ^{[13
]}

Fattal-Valevski, Aviva ^{[14
,15
]}

Shiroma, Naohide ^{[16
]}

Ohfu, Masaharu ^{[17
,18
]}

Moroto, Masaharu ^{[19
,20
]}

Tanda, Koichi ^{[14
,15
]}

Nakagawa, Tomoko ^{[21
]}

Sakakibara, Takafumi ^{[21
]}

Nabatame, Shin ^{[22
]}

Matsuo, Muneaki ^{[23
]}

Yamamoto, Akiko ^{[24
]}

Yukishita, Shoko ^{[6
]}

Inoue, Ken ^{[4
]}

Waga, Chikako ^{[4
]}

Nakamura, Yoko ^{[4
]}

Watanabe, Shoko ^{[25
]}

Ohba, Chihiro ^{[1
]}

Sengoku, Toru ^{[26
]}

Fujita, Atsushi ^{[1
]}

Mitsuhashi, Satomi ^{[1
]}

Miyatake, Satoko ^{[1
,27
]}

Takata, Atsushi ^{[1
]}

Miyake, Noriko ^{[1
]}

Ogata, Kazuhiro ^{[26
]}

Ito, Shuichi ^{[2
,27
]}

Saitsu, Hirotomo ^{[28
]}

Matsuishi, Toyojiro ^{[29
,30
]}

Goto, Yu-ichi ^{[4
,25
]}

Matsumoto, Naomichi ^{[1
]}

机构：

[1] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Kanagawa 2360004, Japan

[2] Yokohama City Univ, Grad Sch Med, Dept Pediat, Yokohama, Kanagawa, Japan

[3] Natl Ctr Hosp, Natl Ctr Neurol & Psychiat, Dept Child Neurol, Tokyo, Japan

[4] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Mental Retardat & Birth Defect Res, Tokyo, Japan

[5] Tama Nagayama Hosp, Nippon Med Sch, Dept Pediat, Tokyo, Japan

[6] Yoshiko Nomura Neurol Clin Children, Tokyo, Japan

[7] Osaka Dev Rehabil Ctr, Div Pediat, Osaka, Japan

[8] Kurume Univ, Sch Med, Dept Pediat & Child Hlth, Fukuoka, Fukuoka, Japan

[9] Osaka Womens & Childrens Hosp, Det Med Genet, Osaka, Japan

[10] Asahikawa Med Univ, Dept Pediat, Asahikawa, Hokkaido, Japan

[11] Kitakyushu Municipal Yahata Hosp, Dept Pediat, Fukuoka, Fukuoka, Japan

[12] Tokyo Metropolitan Neurol Hosp, Dept Neuropediat, Tokyo, Japan

[13] Segawa Mem Neurol Clin Children, Tokyo, Japan

[14] Tel Aviv Univ, Dana Dwek Childrens Hosp, Tel Aviv Med Ctr, Pediat Neurol Unit, Tel Aviv, Israel

[15] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[16] Neurodev Clin Prop, Nishihara, Okinawa, Japan

[17] Okinawa Prefectural Nanbu Med Ctr, Div Child Neurol, Haebaru, Okinawa, Japan

[18] Childrens Med Ctr, Haebaru, Okinawa, Japan

[19] Japanese Red Cross Kyoto Daiichi Hosp, Dept Pediat, Kyoto, Japan

[20] Kyoto Prefectural Chutan Nishi Publ Hlth Ctr, Kyoto, Japan

[21] Nara Med Univ, Dept Pediat, Nara, Japan

[22] Osaka Univ, Grad Sch Med, Dept Pediat, Osaka, Japan

[23] Saga Univ, Fac Med, Dept Pediat, Saga, Japan

[24] Tokyo Metropolitan Tobu Med Ctr Persons Dev & Mul, Div Pediat, Tokyo, Japan

[25] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, MGC, Dept Genome Med Dev, Tokyo, Japan

[26] Yokohama City Univ, Grad Sch Med, Dept Biochem, Yokohama, Kanagawa, Japan

[27] Yokohama City Univ Med, Clin Genet Dept, Yokohama, Kanagawa, Japan

[28] Hamamatsu Univ, Sch Med, Dept Biochem, Hamamatsu, Shizuoka, Japan

[29] St Marys Hosp, Res Ctr Children, Fukuoka, Fukuoka, Japan

[30] St Marys Hosp, Res Ctr Rett Syndrome, Fukuoka, Fukuoka, Japan

来源：

JOURNAL OF MEDICAL GENETICS | 2019年 / 56卷 / 06期

关键词：

DE-NOVO MUTATIONS; IDENTIFICATION; CHILDHOOD; MECP2;

D O I：

10.1136/jmedgenet-2018-105775

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). Methods We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. Results Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of AT Pase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). Conclusions Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

引用

页码：396 / 407

页数：12

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