日本人における常染色体劣性遺伝形式を示す骨系統疾患関連遺伝子バリアント解析による保因者頻度と潜在的な発症者の推定

日本人における常染色体劣性遺伝形式を示す骨系統

疾患関連遺伝子バリアント解析による保因者頻度と

潜在的な発症者の推定

著者

永岡 晋一

学位授与機関

Tohoku University

学位授与番号

11301甲第19118号

URL

http://hdl.handle.net/10097/00129213

】. 3 . 6 . 14 . 15 . 22 . 37 . 47 . 49 . 〜 50 . 51 . 64

】 436 5,000 1 ・ ； ） （ ・ 3.5KJPNv2

3,552 3.5KJPNv2 7,234 100 30 73 3.5KJPNv2 73 InterVar pathogenic benign 5 ） 3 ClinVar HGMD 4 set1 set4 ） Hardy-Weinberg （ Osteogenesis Imperfecta:

OI Ellis-van Creveld Ellis-van Creveld syndrome: EVC

Asphyxiating thoracic dysplasia: ATD ”

3.5KJPNv2 73

82,817

4 ）

set1 13 set2 152 set3 166 set4 198

） 73 52 21 OI 7 24 0.04564 1/3,074 EVC 2 11 0.00056 0.00535 set1 4 1/12,755,102 1/278,790 set1 4 ATD 6 25 0.00761 0.00958 set2 4 1/338,189 1/193,829 set2 4 HPP ALPL 11 0.00843 0.04362 set3 4 1/56,287 1/2,102 set3 4 ・ ”

. 1) 】 2, 3, 4) Osteogenesis imperfecta OI 3, 5) 6, 7) 85 90 】 COL1A1 COL1A2 6, 8) _COL1A1 COL1A2 】 C BMP19)

SERPINH1 FKBP10 PLOD211, 12) SERPINF113) _SEC24D14) SP7 WNT1 CREB3L115, 16, 17) 18) _（ 3, 5) 3)

Asphyxiating thoracic dysplasia ATD Ellis-van Creveld

Ellis-van Creveld dysplasia EvC ciliopathies 19)

ATD 20)

： ciliary intraflagellar transport IFT

DYNC2H1 IFT80 TTC21B IFT140

WDR19 WDR34 IFT172 18, 19) _（

；

22, 23) _{EvC 60%} 24) _EVC24) _EVC225) ₂ 1 ATD EvC （ “ ” Hypophosphatasia HPP ALPL ” ” TNSALP 26, 27) （ ） 28, 29) 30) 31) 1/5,000 32, 33) 2015 ） 18) _{42 436}

OI 1/15,000 20,000 3, 34) EvC 1/60,000 “ 1/200 35) _{ATD 1/100,000 130,000} 22, 36) HPP 1/100,000 1/300,000 26, 37) _1/2,500 38) _{2009 OI 1/22,000 EvC} 1/448,070 ATD HPP 1/64,000 ATD HPP 39) ₁ OI EvC HPP （ 40, 41, 42) _（

next generation sequence NGS

X 18, 46) 46) 1980 1978 3 217,061 33) ₁₉₇₈ 5 349,470 ・ 32) ・ 1980 47)

・ 39) 1989 20 2007 1 20 434,019 1 14,050 。 NGS 43, 44, 45) _{“ ；}

43) _{whole-exome sequencing WES}

45, 48, 49) _･

； ・ ・ ； ） （ ” 3.5KJPNv2 50) ToMMo IMM 51) _3,552

” 3.5KJPNv2 50)

single nucleotide variant SNV INDEL

insertion/deletion

Japanese Multi Omics Reference jMorp

https://jmorp.megabank.tohoku.ac.jp/201905 Yasuda 52) _1KJPN 1KJPN 1000 JPT PCA 1KJPN JPT 1KJPN PCA 1KJPN Tadaka 50) 3.5KJPNv2 ” Genome Aggregation

” 53)

1000 54)

PCA

3.5KJPNv2 JPT

3.5KJPNv2 ”

1 ToMMo ” 3.5KJPNv250) 1990 2016 47) _{1990 2016 26 7,234} 217 100 X 30 2 30 2015 ）18) ₃₀ 2 Mesomelic dysplasia

Pyle Pyle disease 73

2 30 （

OI ATD EvC HPP 4

OI

3, 7) _{EvC ATD Ciliopathy}

（ 19) _ATD 45, 55) _{HPP 。} 。 。 （ 31, 56, 57) _{OI HPP （} ） 58) 4 。 4 448,069 39) 3 95 々 3

2

ToMMo51) _3,552

3.5KJPNv2 ”

50)

59) _{1 3.5KJPNv2}

Valiant Quality Score Recalibration Annovar60)

InterVar61) _{Human Gene Mutation Database HGMD} 62, 63)

InterVar ACMG-AMP 64)

” “ ACMG-AMP

（

28 Pathogenic Benign 5

） InterVar 28

18 pathogenic very strong PVS1 strong PS1,4

moderate PM1,2,4,5 supporting PP2,3,5 benign stand-alone BA1

strong BS1,2 supporting BP1,3,4,6,7 3

PP1,4 benign strong BS3,4 supporting BP2,5

10 de

novo in vitro in vivo

18 PP5 BP6 々 InterVar ClinVar65) _{“ PP5} HGMD 2 “ Pathogenic Benign InterVar 28 18 64) 3 ） 30 73 3.5KJPNv2 59) edge effect 1kb

73 3.5KJPNv2

InterVar 5 pathogenic P likely pathogenic LP variant of uncertain

significant VUS likely benign LB benign B ） P LP

） 3.5KJPNv2 minor allele

frequency MAF 3 ClinVar P

LP ”reported ”

”interpreted ” VUS

MAF < 0.03 ClinVar HGMD ClinVar

”clinvar” ClinVar HGMD ”hgmd” 59) _{73 4} ） ACMG-AMP InterVar P LP ClinVar P LP set1 ）

） set2 set1 ”interpreted ”P LP

） 3 ） VUS MAF <

0.03 ClinVar P LP set2

set3 set4 VUS MAF < 0.03 ClinVar

P LP HGMD DM disease-causing

mutation set3 ） 1 ClinVar

65) _CLINGEN 、 HGMD 62) 4 InterVar MAF<0.03 ” ClinVar HGMD ） InterVar ー ClinVar HGMD

“ set1 set4 ） 4 59) A n A Q n Q 1−Q Hardy-Weinberg 2× 1-Q ×Q = # × %(' − %) 5

3.5KJPNV2 Exome Aggregation

Consortium ExAC; http://exac.broadinstitute.org/ “

Fisher

Microsoft, Redmond, Washington, USA p < 0.05

．

1964

30 73 3.5KJPNv2

82,817 1 73

52 21

IFT80 DYM RAB33B B4GALT7 DMP1 SLC34A3 POP1 SBDS GNS CREB3L1 FKBP10 PPIB SP7 WNT1 PLEKHM1 SNX10 TNFRSF11

TNFSF11 HES7 LFNG MESP2 5 InterVar

MAF<0.03 ” ClinVar HGMD

4 ） 1 Set1 13 10 set2

152 46 set3 166 49 set4

198 52 1 Set1 ）

HGMD DM 12 Set2

25 set3 32 MAF 3 VUS ）

4 Hardy-Weinberg 5 3 2 1 Osteogenesis imperfecta OI 1 BMP1 MIM# 614856 3.5KJPNv2 6 p.Gly209Val

p.Phe277Leu p.Asp284Tyr p.Glu547Gly p.Arg586His p.Gly713Ser

InterVar moderate PM1 PM2 supporting PP2 PP3

likely pathogenic ClinVar HGMD

6 set2 ） 1 6

1 BMP1

0.00084 0.00169 5

610915 PPIB CRTAP 1 c.621+1G>A 2 6 c.621+1G>A InterVar pathogenic PVS1 ClinVar HGMD set2 ） 1 AF= 0.00028 CRTAP 0.00056 5 LEPRE1 1 1 p.Gln576*

p.Gln576* stop gain InterVar pathogenic PVS1

set2 ） 1 0.00014

LEPRE1 0.00028 5

3 FKBP10 MIM# 610968 / SERPINH1 MIM# 613848 / PLOD2 MIM# 609220

FKBP10

SERPINH1 7 6 p.Ser77Leu

p.Ala354Thr InterVar likely

pathogenic set2 ） 1

p.Thr227Ile p.Val256Met p.Ala354Thr 1

p.Ser77Leu 9 p.Val219Met

p.Asn244Ile 2 p.Ala349Val 5

0.00296 SERPINH1

0.00591 5

PLOD2 7 p.Gln553Arg p.Asp507His

p.Arg484His p.Asn457Asp p.Asn399Tyr p.Thr398Ala p.Asp386Asn

InterVar likely pathogenic

set2 ） 1 p.Gln553Arg 64 p.Asn457Asp 42 2 p.Asp386Asn 10 p.Gln553Arg 0.00901 p.Asn457Asp 0.00648 p.Asp386Asn 0.00141 3 ExAC “ ”

” AF= 0 p <

0.001 ExAC HGVD Human

Genetic Variation Database http://www.hgvd.genome.med.kyoto-u.ac.jp/

p.Gln553Arg AF = 0.0087 p.Asn457Asp AF = 0.0029

p.Asp386Asn AF = 0.008 p >

0.05 p.Gln553Arg p.Asn457Asp p.Asp386Asn “

p.Asp507His p.Arg484His p.Asn399Tyr p.Thr398Ala

2 1 1 3 PLOD2 0.03551 5 4 SERPINF1 MIM# 616295 c.284-2A>G 5 6 InterVar PVS1 pathogenic set2 ） 1 0.0007 0.00141 5 5 SEC24D MIM# 616295

p.Gln302* 1 “

InterVar PVS1 pathogenic set2

） AF = 0.00014

0.00028 5

6 WNT1 MIM# 615220 / CREB3L1 MIM# 616229 /SP7 MIM# 613849 WNT1 CREB3L1 SP7 3.5KJPNv2 OI ） 18) _{12 5 PPIB FKBP10} WNT1 CREB3L1 SP7 3.5KJPNv2 5 6 ClinVar HGMD

SEC24D set2 ） Set3 4 ）

0.04564 22 1

1/3,074

1/22,000 3 2

2 Ellis-van Creveld Ellis-van Creveld dysplasia EvC

EVC/ EVC2 MIM# 225500

EVC 3 c.1887-1G>C p.Thr295Ser p.Leu328Phe

6 c.1887-1G>C 1

InterVar pathogenic PVS1 ClinVar

HGMD set2 ） 0.00014

p.Thr295Ser p.Leu328Phe

InterVar VUS HGMD DM set4

） 3 Ren

0.00028 0.00099 EVC

set2 0.00028 set4 0.00281

5

EVC2 8 p.Arg399* p.Trp828* c.1230+1G>C

c.906-2A>C p.Glu846fs p.Arg698* p.Asn361fs p.Arg950Trp set1 3

6 p.Arg399* “ 2

InterVar pathogenic ClinVar P HGMD DM

set1 ） AF = 0.00028 p.Arg399* Ruiz-Perez

67) _{p.Trp828* “ 1}

InterVar pathogenic HGMD DM ClinVar

set2 AF = 0.00014 p.Trp828* Zhang

68)

c.1230+1G>C c.906-2A>C

InterVar pathogenic ClinVar HGMD

0.00014 p.Glu846fs p.Asn361fs ” ”

InterVar likely pathogenic ClinVar

HGMD set2 ） 1

0.00014 p.Arg698* “

1 set2

0.00014 p.Arg950Trp InterVar VUS

ClinVar pathogenic HGMD DM set3

AF = 0.00014 p.Arg950Trp Galdzicka 2002 EvC

25) _{EVC2 set1}

0.00056 set2 0.00226 set3 0.00254 5

EVC EVC2 set1 0.00056 set2

0.00254 set3 0.00282 set4 0.00535

5

1/12,755,102 set1 1/771,307 set2 1/612,557 set3 1/278,790 set4

1/278,790

1/450,000 3 2

3 Asphyxiating thoracic dysplasia ATD

1 DYNC2H1 MIM# 613091 / WDR34 MIM# 615633

DYNC2H1 7 p.Val1840fs p.Glu1894fs

p.Lys2688fs p.Arg3326fs p.Arg3349* c.11277+1G>A p.Arg3004Cys

6 p.Arg3349* c.11277+1G>A “

InterVar pathogenic

set2 ） AF = 0.00014 1

p.Val1840fs p.Glu1894fs p.Lys2688fs and

p.Arg3326fs ” ” p.Glu1894fs

HGMD DM p.Val1840fs p.Lys2688fs p.Arg3326fs

ClinVar HGMD 4 InterVar

likely pathogenic set2 ） p.Glu1894fs 3 AF =

AF = 0.00014 0.00014 000014 p.Arg3004Cys

4 HGMD DM

69) _{p.Arg3004Cys InterVar VUS}

Clinvar VUS HGMD DM set4 ）

AF = 0.00056 DYNC2H1 set2 0.00225 set4 0.00338 5 WDR34 c.1372+2T>C 1 InterVar pathogenic set2 ） 0.00014 set2 0.00028 5

2 IFT80 MIM# 611263 / IFT172 MIM# 615630

IFT80

IFT172 5 c.3229-1G>C c.2116-1G>A

p.Thr663fs p.Arg271* c.571-1G>A 6 5

p.Arg271* “ p.Thr663fs

” ” InterVar

pathogenic c.3229-1G>C c.2116-1G>A p.Arg271* c.571-1G>A

likely pathogenic p.Thr663fs set2 ） 1

0.00141 set2

5

3 IFT140 MIM# 266920 /WDR19 MIM# 614376 / TTC21B MIM# 613819

IFT140 4 2 “

p.Gln998* p.Arg1072* 1 ” ”

p.Tyr923fs 1 p.Gly163Gly

6 p.Gln998* p.Arg1072* p.Tyr923fs InterVar pathogenic

p.Gln998* likely pathogenic p.Arg1072* p.Tyr923fs

ClinVar HGMD set2

） p.Gly163Gly InterVar VUS HGMD DM

70) ₄ 1 0.00085 set2 0.00113 set4 5 WDR19 3 2 c.2165+1G>T c.2782-2A>G 1 ” ” p.Leu211fs 6 c.2165+1G>T c.2782-2A>G

InterVar pathogenic p.Leu211fs likely pathogenic

p.Leu211fs HGMD DM 3 ClinVar set2 ） c.2165+1G>T c.2782-2A>G 0.00028 p.Leu211fs 0.00014 0.00141 set2 5 TTC21B 6 6 p.Glu371* “ c.430-2A>C InterVar pathogenic ” ” p.Tyr1282fs

p.Val1075fs InterVar likely pathogenic 4

p.Arg867Cys pHis566Arg 2

p.Arg867Cys pHis566Arg InterVar VUS

HGMD DM set4 ）

0.00141 set2 0.00197 set4

3.5KJPNv2 7 ATD

set1 0 set2 0.00761 set4

0.00958

1/338,189 set2 1/193,828 set4

1/64,000 3 2

4 ” Hypophosphatasia HPP

ALPL MIM# 241500

ALPL 11 p.Met62Val p.Arg136His

p.Ala177Thr p.Glu191Gly p.Phe327Leu p.His341Arg p.Ile395Val

） HGMD DM 6 p.Arg136His

p.Phe327Leu c.1559delT ClinVar P LP set3

） 8 ClinVar set4 ）

” ” c.1559delT

p.Arg136His p.Glu191Gly p.Phe327Leu

p.His341Arg p.Gly426Ser c.1559delT 71,

72) InterVar p.Phe327Leu AF= 0.00225 c.1559delT AF= 0.00169 72, 73, 74) _{ExAC “} 2 AF= 0 p < 0.001 6 p.Phe327Leu 16 c.1559delT 12 p.Ala177Thr 116 0.01689 ExAC “ ” ” “

p < 0.001 ExAC

AF = 0.0017 HGVD Human Genetic Variation Database

http://www.hgvd.genome.med.kyoto-u.ac.jp/ AF = 0.0132 p > 0.05 p.Ala177Thr “ set3 0.00843 set4 0.04362 1/56,287 set3 1/2,102 set4 1/64,000 3 2

30 39) 59) _{30 73 」} 73 198 52 198 set1 set4 4 ） 1 ClinVar HGMD ） 75, 76, 77)

InterVar ACMG-AMP ClinVar HGMD ” “ set1 set4 4 ） 59) set ） ） set3 4 HPP EvC set3 ） OI ATD set3 ）

ACMG-AMP ClinVar HGMD 3.5KJPNv2 MAF 3 ） 5 MAF 1 0.0198

9.8E-5 MAF 5 0.095 2.2E-3 3 MAF 3 4 4 set OI set2 ） 2 HPP EvC set3 ） set

2 ATD set2 set4 ）

2

OI 3.5KJPNv2 PLOD2

p.Gln553Arg p.Asn457Asp ExAC “

4 set2 1/3,074 1/22,000 2 100 InterVar p.Asn457Asp 2 （ （ ExAC HGVD

2

HPP

p.Ala177Thr p.Ala177Thr set4 ）

set3 HPP 1/56,287 set4 1/2,102 OI HPP 30) set3 1/56,287 ATD 3.5KJPNv2 22 1/338,189 set2 1/193,828 set4 1/64,000 InterVar VUS

IFT80 ATD （ 22, 23) _（ ATD NGS 55) EvC 1/450,000 1/278,790 EvC 78) _{Hardy Weinberg} ClinVar HGMD ACMG-AMP InterVar

pathogenic likely pathogenic

ATD 4 ExAC “ 6 OI ATD ClinVar HGMD ） 75, 76, 77) _{ClinVar HGMD} pathogenic likely pathogenic 5 ClinVar pathogenic HGMD DM

InterVar VUS EvC

p.Arg950Trp HPP p.Arg136His p.Phe327Leu c.1559delT

4 ACMG-AMP

” “

10

InterVar de novo

VUS

） pathogenic likely pathogenic

ALPL p.Phe327Leu c.1559delT 72, 73) p.Phe327Leu c.1559delT 3.5KJPNv2 ExAC “ p < 0.001 c.571G>A c.1133A>T c.571G>A “ HPP 50% c.1133A>T HPP

79) _{c.571G>A c.1133A>T 3.5KJPNv2} ClinVar HGMD 3.5KJPNv2 ” 3.5KJPNv2 3,552 ” 3.5KJPNv2 3.5KJPNv2

OI PPIB FKBP10 WNT1 CREB3L1 SP7 ATD

IFT80

3,552 ”

ACMG-AMP InterVar

10

de novo in vitro in vivo

･ 3.5KJPNv2

Insertion Deletion

X

・ 3.5KJPNv2

（

OI HPP EvC ATD （

。

「

. 〜

OI Osteogenesis imperfecta

ATD Asphyxiating thoracic dysplasia

EvC Ellis-van Creveld dysplasia

HPP Hypophosphatasia

NGS Next generation sequence

WES Whole-exome sequencing

SNV single nucleotide variant

MAF Minor allele frequency

HGMD Human Gene Mutation Database

P pathogenic

LP likely pathogenic

VUS variant of uncertain significant

LB likely benign

B benign

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1. 73 3.5KJPNv250)

）

73 3.5KJPNv2 82,817 InterVar

Pathogenic Benign ） MAF 3%

ClinVar P LP reported

) interpreted ） VUS ClinVar

clinvar” HGMD ”hgmd”

4 ） set1 4 ） 59)

3.5KJPNv2 73

P LP VUS LB B

P_reported

LP_reported LP_ interpretedP_interpreted

p_clinvar lp_clinvar p_hgmd Set1 P_reported LP_reported Set2 Set1 + P_interpreted LP_ interpreted Set3 Set2 + p_clinvar lp_clinvar Set4 Set3 + p_hgmd InterVar LB B 3.5KJPNv2 < 3% > 3% → VUS VUS HGMD ClinVar ( P or LP )

yes no yes no yes no

no yes/DM P ; Pathogenic LP ; Likely pathogenic VUS ; Variants of Uncertain Significance LB ; Likely benign B ; Benign DM ; Disease-causing Mutation

2. OI HPP ATD EVC 39) ₄ 3 set1 set4 1 1.0.E-08 1.0.E-07 1.0.E-06 1.0.E-05 1.0.E-04 5.0.E-04 OI HPP ATD EvC Set1 P LP ”reported”

Set2 Set1 ”interpreted“ P LP Set3 Set2 VUS ClinVer P/LP Set4 Set3 VUS HGMD DM

1. 4 OI EvC ATD HPP 142 5 26 1,919,09434) _650,00022) _7,700,00037) (1/x) 13,515 60,00035) _{130,000 296,154} 20 1 7 7 448,06939) _{448,069 448,069 448,069} (1/x) 22,403 448,069 64,010 64,010 OI 2010 1,919,094 OI 142 ATD 1965 650,000 ATD 5 HPP ” 2006 770,000 HPP 26 39) _{1989 20} 2007 1 20 434,019 1 14,050

2 30 73

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hOihP hOWhP e 525 8C HIMN

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- ( 2 68 ( 26- ( 28 ( )(( 2 - ( 3 28 ( 4 ( ) 8 26 ( ) 2 3 ( ) ( ) 6 8) ( ) ) ( 10 7 ( ) ( 9 7 ( )( ) 60537 ( (( ( ) 2 ( )) ( 8 ( ) ( 4 2 ( ) 81 1 ( ( 81 1 ( ) ( eUTY G KC NKNOKNFN 5 ( (

) cY aTX LK C HKIDOALE NDAH C NLHANFAN 7 ( (

OFBGHDMYTX OFBGHDM N CMKID 96 (

66 ( )( )) 30 ) ( ( ( ( SR d Y chYTX 7PBKLKH NABBEAMFCKNFN 9NODKLDOMKNFN LK C HKBKNOAH C NKNOKNFN

Y V o 2TL L OL P OG 484 ) )(

168 - ( )

168 1 ( ) (

0 HDNO H Ooig 0 HDNO H O OTCN ID - 1 4 ) ( ) )

0 (

0 ( ) (

a yd hro BN IDO IDHGB CTOLH OG PTLD 5 N PD QS 5 5 68 ( ( )

6 ( ( 4 ( ( ))) ) (( 5 6 ( ( ) 8 H C p 8 34367 OT CN ID 8 H C 0 94 ( ) (( 558 ( 558 ( ( ) PHDT -GSHDNoig PHDT -GSHDN OT CN ID 87 )

mt e x hro 7P OL CTH IDE DLGL TOD H CTOLH OG 7 50 74

q hro G OPN L GB CTOLH OG 4 ( ( () (

5 ( ) (

- - ( (

u p hro TOODEID P H CTOLH OG 2 81 (

s vo PDH OPD ED DOGO PTLD 7 4 ( ( () (

Xlno

0HHGO R NDRDHC hro

( DOAQMQ GOoig

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CN DBP CDNI H CTOLH OG 0HHGO R NDRDHC

) t x cx hro

b q cx hro

TEERD 5DHB G N H QOD hro

DOAQMQ GO CTOLH OG

L CTH DLG IDP L TOD H CTOLH OG O 05

5DP L TOD H CTOLH OG

( cg gWT md he 9 JD C FPC COBJ ECOH NJFB BS G F 99 0 ;10 FNE JD C FPC NE J NES 5;9 ( 0 7 4 ( ) ( 0 ( ( ( ( 52 ( )) ( ( 52 ) ( ) ( ( ( 52 ( ( (( 0 ( ( )( ( ( Yd he IFJHCN ES C G BS G F 36-9SGCd he 9SGC BF C C

J FIJ eb J FIJ SIB JHC 8 ( ) (

3. OI HPP ATD EVC 95

95 * **

* * Set1 Set2 Set3 Set4

OI 20 4.5 E-05 2.5 E-05 6.4 E-05 0 3.3 E-04 3.3 E-04 3.3 E-04

HPP 7 1.6 E-05 4.0 E-06 2.7 E-05 0 0 1.8 E-05 4.8 E-04

ATD 7 1.6 E-05 4.0 E-06 2.7 E-05 0 3.0 E-06 3.0 E-06 5.2 E-06

EvC 1 2.2 E-06 -2.1 E-06 6.6 E-06 7.8 E-08 1.3 E-06 1.6 E-06 3.6 E-06

448,069 39)

4. InterVar 18/28

Li, Q., Wang, K. (2017) InterVar: Clinical Interpretation of Genetic Variants by the

2015 ACMG-AMP Guidelines. Am J Hum Genet, 100, 267-280.61)

- 271 63 761 5 761 57 -) 5 E( A C GA G 0 / 51 7 361 0 / 51 6316 -6 -476 ) 5 ( % 761 7 361 51/5

5. 73 *set1 set4 1 7 60 0 * * * . , 3 69 0 382 15 0 381 0. * * * 8 . 0 6 7 08 6. , 9 54 8A B LCDJMK HEIF

89 359 3 59 9 09 5 1 5 3 9 90 3 5 . 85 69 4 73 204 8 9 87 95 18 5.89. 5.9. 92 7 63 33 0 9 3.5 4 97 373

57 57 3 579 5 3 9 4 5 9 83 447 447 769 63 3 4 9 0 7 1 7 5 0 9 1. 1. 1. 9 2 969

6. 73

* P; pathogenic, LP; likely pathogenic, VUS; variant of significant, LB; likely benign, B; benign, *2 _{DM; disease-causing mutation}

*3 _{3 1}

Chr Position

(GRCh37/hg19) RefRef Het AltAlt ClinVar* HGMD*2

c.G626T:p.Gly209Val missense 8 22034548 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.C831A:p.Phe277Leu missense 8 22035465 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.G850T:p.Asp284Tyr missense 8 22037231 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.A1640G:p.Glu547Gly missense 8 22052975 rs764357220 3551 1 0 0.00014 8.4.E-06 0.0001 0 0 LP - - LP_interpreted 2

c.G1757A:p.Arg586His missense 8 22053092 rs755936351 3551 1 0 0.00014 3.4.E-05 0.0001 2.0.E-04 0 LP - - LP_interpreted 2

c.G2137A:p.Gly713Ser missense 8 22059345 rs148687489 3551 1 0 0.00014 6.8.E-05 0 0 0 LP - - LP_interpreted 2

CRTAP c.621+1G>A splicing 3 33161986 rs775720622 3550 2 0 0.00028 1.3.E-05 0.0002 0 0 P - - P_interpreted 2

LEPRE1(P3H1) c.C1726T:p.Gln576* stopgain 1 43213983 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.C230T:p.Ser77Leu missense 11 75277624 . 3543 9 0 0.00127 . . . . LP - - LP_interpreted 2

c.G655A:p.Val219Met missense 11 75279808 . 3550 2 0 0.00028 . . . . LP - - LP_interpreted 2

c.C680T:p.Thr227Ile missense 11 75279833 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.A731T:p.Asn244Ile missense 11 75279993 . 3550 2 0 0.00028 . . . . LP - - LP_interpreted 2

c.G766A:p.Val256Met missense 11 75280028 rs749664592 3551 1 0 0.00014 8.2.E-06 0 0 0 LP - - LP_interpreted 2

c.C1046T:p.Ala349Val missense 11 75282917 . 3547 5 0 0.00070 . . . . LP - - LP_interpreted 2

c.G1060A:p.Ala354Thr missense 11 75282931 rs369550626 3551 1 0 0.00014 1.7.E-05 0 0 3.0.E-05 LP - - LP_interpreted 2

c.A1658G:p.Gln553Arg missense 3 145794588 rs148051196 3488 64 0 0.00901 1.0.E-04 0.0014 0 0 LP - - LP_interpreted 2

c.G1519C:p.Asp507His missense 3 145795693 . 3550 2 0 0.00028 . . . . LP - - LP_interpreted 2

c.G1451A:p.Arg484His missense 3 145796952 rs142909885 3551 1 0 0.00014 3.0.E-04 0.0001 0 4.0.E-04 LP - - LP_interpreted 2

c.A1369G:p.Asn457Asp missense 3 145797034 rs770173711 3508 42 2 0.00648 1.7.E-05 0.0002 0 0 LP - - LP_interpreted 2

c.A1195T:p.Asn399Tyr missense 3 145802993 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.A1192G:p.Thr398Ala missense 3 145802996 . 3549 3 0 0.00042 . . . . LP - - LP_interpreted 2

c.G1156A:p.Asp386Asn missense 3 145803032 rs200189099 3542 10 0 0.00141 1.0.E-04 0.0021 0 0 LP - - LP_interpreted 2

SERPINF1 c.284-2A>G splicing 17 1674321 rs113947687 3547 5 0 0.00070 . . . . P - - P_interpreted 2

SEC24D c.C904T:p.Gln302* stopgain 4 119727007 rs770892912 3551 1 0 0.00014 2.5.E-05 0.0002 0 1.5.E-05 P - - P_interpreted 2

ExAC SERPINH1 BMP1 PLOD2 Set *3 OI *3 ExAC 3.5KJPN 3.5KJPN dbSNP ExAC InterVar* ExAC

c.1887-1G>C splicing 4 5798748 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.C884G:p.Thr295Ser misense 4 5747013 rs754532508 3550 2 0 0.00028 6.6.E-05 0.0009 0 0 VUS - DM p_hgmd 4

c.C982T:p.Leu328Phe misense 4 5749917 rs199916502 3545 7 0 0.00099 3.0.E-04 0.0045 0 1.5.E-05 VUS - DM p_hgmd 4

c.C1195T:p.Arg399* stopgain 4 5642516 rs137852924 3550 2 0 0.00028 3.3.E-05 0 0 1.5.E-05 P P DM P_reported 1

c.G2484A:p.Trp828* stopgain 4 5624281 rs770918273 3551 1 0 0.00014 1.8.E-05 0.0002 0 0 P - DM P_interpreted 2

c.1230+1G>C splicing 4 5642240 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.906-2A>C splicing 4 5642567 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.C2848T:p.Arg950Trp misense 4 5586559 rs137852928 3551 1 0 0.00014 2.0.E-04 0 0 2.0.E-04 VUS P DM p_clinvar 3

c.2536delG:p.Glu846fs frameshift deletion 4 5620375 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.C2092T:p.Arg698* stopgain 4 5624673 rs781623802 3551 1 0 0.00014 1.7.E-05 0.0001 2.0.E-04 0 LP - - LP_interpreted 2

c.1082dupA:p.Asn361fs frameshift insertion 4 5664896 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.5518_5519insTA:p.Val1

840fs frameshift insertion 11 103043994 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.5681_5682del:p.Glu189

4fs frameshift deletion 11

103046970-103046971rs767846762 3549 3 0 0.00042 4.9.E-05 0.0016 0 0 LP - DM LP_interpreted 2

c.8062delA:p.Lys2688fs frameshift deletion 11 103070179 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.9977delG:p.Arg3326fs frameshift deletion 11 103116017 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.C10045T:p.Arg3349* stopgain 11 103116085 rs751891969 3551 1 0 0.00014 2.7.E-05 0 2.0.E-04 0 P - - P_interpreted 2

c.11277+1G>A splicing 11 103173983 . 3551 1 0 0.00014 . . 0 0 P - - P_interpreted 2

c.C9010T:p.Arg3004Cys missense 11 103091415 rs752449341 3548 4 0 0.00056 8.3.E-06 0 . . VUS - DM p_hgmd 4

WDR34 c.1372+2T>C splicing 9 131396503 rs758936528 3551 1 0 0.00014 8.4.E-06 0 0 1.5.E-05 P - - P_interpreted 2

c.3229-1G>C splicing 2 27679521 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.2116-1G>A splicing 2 27684704 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.1989delC:p.Thr663fs frameshift deletion 2 27685997 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.C811T:p.Arg271* stopgain 2 27702991 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.571-1G>A splicing 2 27704128 rs775935517 3551 1 0 0.00014 2.1.E-05 0.0001 0 1.9.E-05 P - - P_interpreted 2

c.C2992T:p.Gln998* stopgain 16 1574790 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.C3214T:p.Arg1072* stopgain 16 1573885 . 3551 1 0 0.00014 . . . . LP - - LP_interpreted 2

c.C489T:p.Gly163Gly synonymous SNV 16 1642470 rs776597097 3551 1 0 0.00014 . . . 1.5.E-05 VUS - DM p_hgmd 4

c.2767_2768del:p.Tyr923

fs frameshift deletion 16

1575886-1575889rs769075694 3551 1 0 0.00014 0.0.E+00 . 0 0 LP - - LP_interpreted 2

c.634dupT:p.Leu211fs frameshift insertion 4 39206803 . 3550 2 0 0.00028 . . . . LP - DM LP_interpreted 2

c.2165+1G>T splicing 4 39246173 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.2782-2A>G splicing 4 39269613 rs753291151 3550 2 0 0.00028 2.3.E-05 0.0004 0 0 P - - P_interpreted 2

c.G1111T:p.Glu371* stopgain 2 166786234 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.430-2A>C splicing 2 166799853 . 3551 1 0 0.00014 . . . . P - - P_interpreted 2

c.3845_3846del:p.Tyr128

2fs frameshift deletion 2

166732702-166732703. 3551 1 0 0.00014 . . 0 0 LP - - LP_interpreted 2

c.3224_3225insGAAACT

GT:p.Val1075fs frameshift insertion 2 166747027 . 3550 2 0 0.00028 . . 2.1.E-03 8.0.E-04 LP - - LP_interpreted 2

c.C2599T:p.Arg867Cys missense 2 166758390 rs746700857 3551 1 0 0.00014 8.3.E-06 0 . . VUS - DM p_hgmd 4

c.A1697G:pHis566Arg missense 2 166773969 rs146320075 3551 1 0 0.00014 6.0.E-04 0 . . VUS VUS DM p_hgmd 4

EVC EVC2 ATD DYNC2H1 IFT172 IFT140 WDR19 TTC21B

1 21887592 . 3551 1 0 0.00014 . . . missense c.A184G:p.Met62Val VUS - DM p_hgmd 1 21889712 rs121918011 3550 2 0 0.00028 2.0.E-04 0 0 missense c.G407A:p.Arg136His VUS P|LP DM p_clinvar 1 21890590 rs199669988 3434 116 2 0.01689 1.0.E-04 . . missense c.G529A:p.Ala177Thr VUS - DM p_hgmd 1 21890633 . 3551 1 0 0.00014 . . . missense c.A572G:p.Glu191Gly VUS - DM p_hgmd 1 21900274 rs121918010 3536 16 0 0.00225 5.8.E-05 0 0 missense c.T979C:p.Phe327Leu VUS P|P DM p_clinvar 1 21902250 . 3551 1 0 0.00014 . . . missense c.A1022G:p.His341Arg VUS - DM p_hgmd 1 21902411 rs772682471 3551 1 0 0.00014 8.2.E-06 0 0 missense c.A1183G:p.Ile395Val VUS - DM p_hgmd 1 21903083 . 3551 1 0 0.00014 . . . missense c.G1258A:p.Gly420Ser VUS - DM p_hgmd 1 21903101 rs770548228 3551 1 0 0.00014 8.2.E-06 0 3.0.E-04 missense c.G1276A:p.Gly426Ser VUS - DM p_hgmd 1 21903132 . 3551 1 0 0.00014 . 0 0 missense c.A1307G:p.Tyr436Cys VUS - DM p_hgmd 1 21904125 rs387906525 3540 12 0 0.00169 2.1.E-05 0 0 frameshift deletion c.1559delT:p.Leu520fs VUS P|P DM p_clinvar

ALPL