Knowledge base for genomic medicine in Japanese
掲載日: 2019/10/10更新日: 2020/08/24
遺伝性難聴
小児・神経疾患
MedGen ID
指定難病等
ガイドライン等
要注意の転帰
聴力消失の進行
検査の保険適用
あり
概念・疫学

先天性難聴は、新生児1,000人に1人の割合で発症する、先天性疾患の中で頻度が高い疾患の一つである。その原因は多岐にわたるが、最も高頻度に認められるのは遺伝子変異による遺伝性難聴によるもので、50%以上の症例に関与していると考えられている (Lancet. 2005. PMID: 15752533) 。遺伝形式から、常染色体優性遺伝形式、常染色体劣性遺伝形式、X連鎖遺伝形式、ミトコンドリア遺伝に分類されるが、70-80%は両親ともに難聴がなく、子どもに難聴が生じる常染色体劣性遺伝である。また、難聴の他に随伴症状を伴うか否かで、非症候性難聴 (外耳の目にみえる奇形や関連疾患がない場合) と症候性難聴 (外耳やその他の器官の奇形及びその他の臓器系の疾患を伴う場合) に分類される。非症候性難聴は遺伝性難聴の約70%を占め、残りの30%を占める症候性難聴には約400種類以上の疾患群が知られている。症候性難聴の多くは難聴以外の症状からも診断が可能であり、Alport症候群、branchio-oto-renal (BOR) 症候群、Jervell and Lange-Nielsen症候群、Norrie症候群、Pendred症候群、Stickler症候群、Treacher Collins症候群、User症候群、Waardenburg症候群などは各々原因遺伝子が特定されている。

遺伝性難聴は原因遺伝子によって、難聴の発症年齢、聴力レベル、聴力像、進行性の有無、随伴症状の有無、治療法の効果が異なることが明らかになってきている。それゆえ、遺伝学的検査によって難聴の正確な診断をつけることが重要であると考えられている。わが国では、信州大学が中心となって2008年7月に「先天性難聴の遺伝子診断」が先進医療として認められ、現在は保険診療で19遺伝子154変異の遺伝学的検査が実施できる。

予後

難聴を伴う遺伝性症候群が400以上報告されており、各疾患ごとに聴力低下の進行の程度は様々である。

治療

現時点では疾患そのものを治療する有効な治療法はなく、補聴器あるいは人工内耳による補聴が有用である。

Genes
Gene symbolOMIMSQM scoring*
Genomics England
PanelApp
PhenotypeVariant information
DIAPH1124900N/ADFNA1 (AD)https://omim.org/allelicVariants/602121
KCNQ4600101N/ADFNA2A (AD)https://omim.org/allelicVariants/603537
GJB3612644N/ADFNA2B (AD)https://omim.org/allelicVariants/603324
GJB2601544N/ADFNA3A (AD)https://omim.org/allelicVariants/121011
GJB6612643N/ADFNA3B (AD)https://omim.org/allelicVariants/604418
MYH14600652N/ADFNA4A (AD)https://omim.org/allelicVariants/608568
CEACAM16614614N/ADFNA4B (AD)https://omim.org/allelicVariants/614591
GSDME (DFNA5)600994N/ADFNA5 (AD)https://omim.org/allelicVariants/608798
WFS1600965N/ADFNA6/14/38 (AD)https://omim.org/allelicVariants/606201
LMX1A601412N/ADFNA7 (AD)https://omim.org/allelicVariants/600298
TECTA601543N/ADFNA8/12 (AD)https://omim.org/allelicVariants/602574
COCH601369N/ADFNA9 (AD)https://omim.org/allelicVariants/603196
EYA4601316N/ADFNA10 (AD)https://omim.org/allelicVariants/603550
MYO7A601317N/ADFNA11 (AD)https://omim.org/allelicVariants/276903
COL11A2601868N/ADFNA13 (AD)https://omim.org/allelicVariants/120290
POU4F3602459N/ADFNA15 (AD)https://omim.org/allelicVariants/602460
DFNA16603964N/ADFNA16 (AD)N/A
MYH9603622N/ADFNA17 (AD)https://omim.org/allelicVariants/160775
DFNA18606012N/ADFNA18 (AD)N/A
ACTG1604717N/ADFNA20/26 (AD)https://omim.org/allelicVariants/102560
DFNA21607017N/ADFNA21 (AD)N/A
MYO6606346N/ADFNA22 (AD)https://omim.org/allelicVariants/600970
SIX1605192N/ADFNA23 (AD)https://omim.org/allelicVariants/601205
DFNA24606282N/ADFNA24 (AD)N/A
SLC17A8605583N/ADFNA25 (AD)https://omim.org/allelicVariants/607557
REST612431N/ADFNA27 (AD)https://omim.org/allelicVariants/600571
GRHL2608641N/ADFNA28 (AD)https://omim.org/allelicVariants/608576
DFNA30606451N/ADFNA30 (AD)N/A
DFNA31608645N/ADFNA31 (AD)N/A
DFNA33614211N/ADFNA33 (AD)N/A
NLRP3617772N/ADFNA34 (AD)https://omim.org/allelicVariants/606416
TMC1606705N/ADFNA36 (AD)https://omim.org/allelicVariants/606706
COL11A1618533N/ADFNA37 (AD)https://omim.org/allelicVariants/120280
DSPP605594N/ADFNA39, with dentinogenesis (AD)https://omim.org/allelicVariants/125485
CRYM616357N/ADFNA40 (AD)https://omim.org/allelicVariants/123740
P2RX2608224N/ADFNA41 (AD)https://omim.org/allelicVariants/600844
DFNA43608394N/ADFNA43 (AD)N/A
CCDC50607453N/ADFNA44 (AD)https://omim.org/allelicVariants/611051
DFNA47608652N/ADFNA47 (AD)N/A
MYO1A (DFNA48) 607841N/ADFNA48 (AD)N/A
DFNA49608372N/ADFNA49 (AD)N/A
MIR96613074N/ADFNA50 (AD)https://omim.org/allelicVariants/611606
TJP2 (DFNA51)613558N/ADFNA51 (AD)N/A
POU4F3 (DFNA52)607683N/ADFNA52 (AD)N/A
DFNA53608372N/ADFNA53 (AD)N/A
DFNA54608372N/ADFNA54 (AD)N/A
TNC615629N/ADFNA56 (AD)https://omim.org/allelicVariants/187380
DFNA58615654N/ADFNA58 (AD)N/A
DFNA59612642N/ADFNA59 (AD)N/A
DIABLO614152N/ADFNA64 (AD)https://omim.org/allelicVariants/605219
TBC1D24616044N/ADFNA65 (AD)https://omim.org/allelicVariants/613577
CD164616969N/ADFNA66 (AD)https://omim.org/allelicVariants/603356
OSBPL2616340N/ADFNA67 (AD)https://omim.org/allelicVariants/606731
HOMER2616707N/ADFNA68 (AD)https://omim.org/allelicVariants/604799
KITLG616697N/ADFNA69 (AD)https://omim.org/allelicVariants/184745
MCM2616968N/ADFNA70 (AD)https://omim.org/allelicVariants/116945
DMXL2617605N/ADFNA71 (AD)https://omim.org/allelicVariants/612186
SLC44A4617606N/ADFNA72 (AD)https://omim.org/allelicVariants/606107
PTPRQ617663N/ADFNA73 (AD)https://omim.org/allelicVariants/603317
PDE1C618140N/ADFNA74 (AD)https://omim.org/allelicVariants/602987
TRRAP618778N/ADFNA75 (AD)https://omim.org/allelicVariants/603015
PLS1618787N/ADFNA76 (AD)https://omim.org/allelicVariants/602734
ABCC1618915N/ADFNA77 (AD)https://omim.org/allelicVariants/158343
GJB2220290N/ADFNB1A (AR, DD)https://omim.org/allelicVariants/121011
GJB3220290N/ADeafness, digenic, GJB2/GJB3 (AR, DD)https://omim.org/allelicVariants/603324
GJB6220290N/ADeafness, digenic, GJB2/GJB6https://omim.org/allelicVariants/604418
GJB6612645N/ADFNB1B (AR)https://omim.org/allelicVariants/604418
MYO7A600060N/ADFNB2 (AR)https://omim.org/allelicVariants/276903
MYO15A600316N/ADFNB3 (AR)https://omim.org/allelicVariants/602666
SLC26A4600791N/ADFNB4, with enlarged vestibular aqueduct (AR)https://omim.org/allelicVariants/605646
DFNB5600792N/ADFNB5 (AR)N/A
TMIE600971N/ADFNB6 (AR)https://omim.org/allelicVariants/607237
TMC1600974N/ADFNB7 (AR)https://omim.org/allelicVariants/606706
TMPRSS3601072N/ADFNB8/10 (AR)https://omim.org/allelicVariants/605511
OTOF601071N/ADFNB9 (AR)https://omim.org/allelicVariants/603681
CDH23601386N/ADFNB12 (AR)https://omim.org/allelicVariants/605516
ATP2B2601386N/ADFNB12, modifier of (AR)https://omim.org/allelicVariants/108733
DFNB13603098N/ADFNB13 (AR)N/A
DFNB14603678N/ADFNB14 (AR)N/A
GIPC3601869N/ADFNB15 (AR)https://omim.org/allelicVariants/608792
STRC603720N/ADFNB16 (AR)https://omim.org/allelicVariants/606440
DFNB17603010N/ADFNB17 (AR)N/A
USH1C602092N/ADFNB18A (AR)https://omim.org/allelicVariants/605242
OTOG614945N/ADFNB18B (AR)https://omim.org/allelicVariants/604487
DFNB20604060N/ADFNB20 (AR)N/A
TECTA603629N/ADFNB21 (AR)https://omim.org/allelicVariants/602574
OTOA607039N/ADFNB22 (AR)https://omim.org/allelicVariants/607038
PCDH15609533N/ADFNB23 (AR)https://omim.org/allelicVariants/605514
RDX611022N/ADFNB24 (AR)https://omim.org/allelicVariants/179410
GRXCR1613285N/ADFNB25 (AR)https://omim.org/allelicVariants/613283
GAB1605428N/ADFNB26 (AR)https://omim.org/allelicVariants/604439
DFNB27605818N/ADFNB27 (AR)N/A
TRIOBP609823N/ADFNB28 (AR)https://omim.org/allelicVariants/609761
CLDN14614035N/ADFNB29 (AR)https://omim.org/allelicVariants/605608
MYO3A607101N/ADFNB30 (AR)https://omim.org/allelicVariants/606808
WHRN607084N/ADFNB31 (AR)https://omim.org/allelicVariants/607928
CDC14A608653N/ADFNB32, with or without immotile sperm (AR)https://omim.org/allelicVariants/603504
DFNB33607239N/ADFNB33 (AR)N/A
ESRRB608565N/ADFNB35 (AR)https://omim.org/allelicVariants/602167
ESPN609006N/ADFNB36 (AR)https://omim.org/allelicVariants/606351
MYO6607821N/ADFNB37 (AR)https://omim.org/allelicVariants/600970
DFNB38607239N/ADFNB38 (AR)N/A
HGF608265N/ADFNB39 (AR)https://omim.org/allelicVariants/142409
DFNB40608264N/ADFNB40 (AR)N/A
ILDR1609646N/ADFNB42 (AR)https://omim.org/allelicVariants/609739
ADCY1610154N/ADFNB44 (AR)https://omim.org/allelicVariants/103072
DFNB45612433N/ADFNB45 (AR)N/A
DFNB46609647N/ADFNB46 (AR)N/A
DFNB47609946N/ADFNB47 (AR)N/A
CIB2609439N/ADFNB48 (AR)https://omim.org/allelicVariants/605564
MARVELD2610153N/ADFNB49 (AR)https://omim.org/allelicVariants/610572
DFNB51609941N/ADFNB51 (AR)N/A
COL11A2609706N/ADFNB53 (AR)https://omim.org/allelicVariants/120290
DFNB55609952N/ADFNB55 (AR)N/A
PDZD7618003N/ADFNB57 (AR)https://omim.org/allelicVariants/612971
PJVK610220N/ADFNB59 (AR)https://omim.org/allelicVariants/610219
SLC26A5613865N/ADFNB61 (AR)https://omim.org/allelicVariants/604943
DFNB62610143N/ADFNB62 (AR)N/A
LRTOMT611451N/ADFNB63 (AR)https://omim.org/allelicVariants/612414
DFNB65610248N/ADFNB65 (AR)N/A
DCDC2610212N/ADFNB66 (AR)https://omim.org/allelicVariants/605755
LHFPL5610265N/ADFNB67 (AR)https://omim.org/allelicVariants/609427
S1PR2610419N/ADFNB68 (AR)https://omim.org/allelicVariants/605111
PNPT1614934N/ADFNB70 (AR)https://omim.org/allelicVariants/610316
DFNB71612789N/ADFNB71 (AR)N/A
BSND602522N/ASensorineural deafness with mild renal dysfunction (AR)https://omim.org/allelicVariants/606412
MSRB3613718N/ADFNB74 (AR)https://omim.org/allelicVariants/613719
SYNE4615540N/ADFNB76 (AR)https://omim.org/allelicVariants/615535
LOXHD1613079N/ADFNB77 (AR)https://omim.org/allelicVariants/613072
TPRN613307N/ADFNB79 (AR)https://omim.org/allelicVariants/613354
GPSM2604213N/ADFNB82 (AR)https://omim.org/allelicVariants/609245
DFNB83613685N/ADFNB83 (AR)N/A
PTPRQ613391N/ADFNB84A (AR)https://omim.org/allelicVariants/603317
OTOGL614944N/ADFNB84B (AR)https://omim.org/allelicVariants/614925
DFNB85613392N/ADFNB85 (AR)N/A
TBC1D24614617N/ADFNB86 (AR)https://omim.org/allelicVariants/613577
ELMOD3615429N/ADFNB88 (AR)https://omim.org/allelicVariants/615427
KARS613916N/ADFNB89 (AR)https://omim.org/allelicVariants/601421
SERPINB6613453N/ADFNB91 (AR)https://omim.org/allelicVariants/173321
CABP2614899N/ADFNB93 (AR)https://omim.org/allelicVariants/607314
NARS2618434N/ADFNB94 (AR)https://omim.org/allelicVariants/612803
DFNB96614414N/ADFNB96 (AR)N/A
MET616705N/ADFNB97 (AR)https://omim.org/allelicVariants/164860
TSPEAR614861N/ADFNB98 (AR)https://omim.org/allelicVariants/612920
TMEM132E618481N/ADFNB99 (AR)https://omim.org/allelicVariants/616178
PPIP5K2618422N/ADFNB100 (AR)https://omim.org/allelicVariants/611648
GRXCR2615837N/ADFNB101 (AR)https://omim.org/allelicVariants/615762
EPS8615974N/ADFNB102 (AR)https://omim.org/allelicVariants/600206
CLIC5616042N/ADFNB103 (AR)https://omim.org/allelicVariants/607293
RIPOR2616515N/ADFNB104 (AR)https://omim.org/allelicVariants/611410
EPS8L2617637N/ADFNB106 (AR)https://omim.org/allelicVariants/614988
WBP2617639N/ADFNB107 (AR)https://omim.org/allelicVariants/606962
ROR1617654N/ADFNB108 (AR)https://omim.org/allelicVariants/602336
ESRP1618013N/ADFNB109 (AR)https://omim.org/allelicVariants/612959
COCH618094N/ADFNB110 (AR)https://omim.org/allelicVariants/603196
MPZL2618145N/ADFNB111 (AR)https://omim.org/allelicVariants/604873
BDP1618257N/ADFNB112 (AR)https://omim.org/allelicVariants/607012
CEACAM16618410N/ADFNB113 (AR)https://omim.org/allelicVariants/614591
GRAP618456N/ADFNB114 (AR)https://omim.org/allelicVariants/604330
SPNS2618457N/ADFNB115 (AR)https://omim.org/allelicVariants/612584
KCNJ10600791N/AEnlarged vestibular aqueduct, digenic (AR)https://omim.org/allelicVariants/602208
FOXI1600791N/AEnlarged vestibular aqueduct (AR)https://omim.org/allelicVariants/601093
PRPS1304500N/ADFNX1 (XL)https://omim.org/allelicVariants/311850
POU3F4304400N/ADFNX2 (XLR)https://omim.org/allelicVariants/300039
DFNX3300030N/ADFNX3 (XLR)N/A
SMPX300066N/ADFNX4 (XLD)https://omim.org/allelicVariants/300226
AIFM1300614N/ADFNX5 (XLR)https://omim.org/allelicVariants/300169
COL4A6300914N/ADFNX6 (XLR)https://omim.org/allelicVariants/303631
GPRASP2301018N/ADFNX7 (XLR)https://omim.org/allelicVariants/300969
*ClinGen Actionability Working GroupのSemi-quantitative Metric (SQM) scoring、Outcome/Intervention Pairに関する情報は https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/ を参照。
欧米人での遺伝子頻度

常染色体優性の症候性難聴において、Waardenburg症候群 (WS) I型とIII型ではPAX3、WSII型の一部の症例はMITF、WSIV型はEDNRB、EDN3、SOX10遺伝子の病的バリアントにより発症するが頻度情報の報告は見当たらない。鰓弓耳腎症候群の表現型が認められる家系の約40%でEYA1遺伝子の病的バリアントが確認される。Stickler症候群はCOL2A1、COL11A1、COL11A2遺伝子の病的バリアントにより発症し、神経繊線維腫症2型はNF2遺伝子変異により発症するが、いずれも頻度情報の報告は見当たらない。常染色体劣性の症候性難聴において、Pendred症候群では家系の約50%でSLC26A4遺伝子の病的バリアントが同定される。X連鎖性症候性難聴であるMohr-Tranebjaerg症候群の原因遺伝子はTIMM8Aであるが頻度情報の報告は見当たらない。非症候性難聴における遺伝子頻度は報告されていないようである(GeneReviewsより引用)。

日本人での遺伝子頻度

日本人の常染色体優性遺伝形式をとる感音性難聴患者75名に対して既知の難聴遺伝子の解析を行った結果、46名 (61.3%) に少なくとも1つの候補となる病的バリアントを認めたという報告がある (PLoS One. 2016. PMID: 27911912)。日本人先天性難聴患者のうち約20%にGJB2遺伝子の病的バリアントが見出され、一般健常者の保因者頻度が約1/50である。また、前庭水管拡大を伴う難聴症例の80-90%でSLC26A4遺伝子の病的バリアントが検出され、日本人先天性難聴患者のうち2番目に頻度が高い (小児科診療. 1123-1130. 2013)。

掲載日: 2019/10/10更新日: 2020/08/24