Characterising X-linked Inherited Retinal Disease in New Zealand identifies unique population demographics and genotypes.

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Characterising X-linked Inherited Retinal Disease in

New Zealand identifies unique population demographics and genotypes.

Andrea L Vincent

^{1, 2}

Eileen Song

¹

Shilpa Kuruvilla

^{1, 2}

Naz Raoof

^{1, 2}

Katherine van Bysterveldt

¹

Verity F Oliver

¹

1.Ophthalmology,New Zealand National Eye Centre, University of Auckland, 2.Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand;

Acknowledgements: This work was supported by funding from :Save Sight Society of New Zealand, Retina NZ and University of Auckland PBRF.

Purpose: To characterize the spectrum of X-linked inherited retinal dystrophy (XL-IRD), and to establish a genotype-phenotype correlation within the New Zealand population.

Methods: Probands with XL-IRD (rod-cone dystrophy RP, choroideraemia CHM, congenital stationary night blindness CSNB, retinoschisis RS, blue cone monochromatism BCM, and ocular albinism OA) were identified through family history and positive gene testing, from the 652 patients recruited in the IRD Database. Familial segregation and clinical data for affected male and obligate carrier females was undertaken. Bioinformatics of novel variants included pathogenicity prediction and frequency in population databases. Reported mutations were identified in LOVD.

Results

X-Linked inherited retinal disease was molecularly proven in 42 probands. (XLRP n=19, CHM n=7, CSNB n=5, XLRS n=7, BCM n=2, XLOA n=2), and segregation confirmed in family members where available.

XLRP: 17 unique pathogenic variants were present, of which 10 (58.8%) were not previously described. Mutations in exon ORF15 of RPGR accounted for only 31% (6/19) of XLRP. One novel ORF15 change in a NZ Māori family, segregated with disease in 18 family members Figure 1, 2). Keratoconus also was observed co-segregating with the variant.

Two reportedly unrelated Caucasian families had the same novel mutation (RPGR, c.248-10A>G). One novel RP2 mutation was identified.

Novel variants were present in all Polynesian/NZ Māori families (n=4).

Five families showed significant manifestations in female carriers,(Figure 1,2,3) and 2/5 were initially diagnosed with dominant disease.

CHM: 57% of variants were novel, and 57% were indels.

XLCSNB: disease was attributable to CACNA1F in 80% (4/5) families.

XLRS: 43% of variants were novel, including a large deletion of exon 1.

Conclusion

A knowledge of regional IRD genotypes and disease manifestation facilitates diagnosis for patients, in addition to using a targeted strategy for gene identification. In an era where clinical trials for some XL-IRD are already underway, a timely diagnosis is necessary.

The spectrum of genotypes in an XL-IRD New Zealand population differs significantly that reported in other populations. The majority of variants identified were unique, with 58.8% of XLRP changes not previously reported. The frequency of ORF15 variants in XLRP was only 33%, suggesting screening RPGR prior to ORF15 is a more cost effective strategy in our population. Significant disease manifestation in female carriers was observed, consistent with the observation that XLRP may mimic autosomal dominant inheritance.

This study highlights the importance of local knowledge in retinal diseases, to optimize diagnosis, management, and ultimately treatment.

CR : ALV none, ES none, SK none, NR none, KvB none, VFO none,

#2770 - B0097

Gene Ethnicity location Molecular Diagnosis Protein prediction Effect # family

members Segregation Novel GnomAD

RP2 1 Maori exon4 c.945_946insT p.(Asn316Ter) insertion,

terminating 2 Yes Novel ABSENT

RPGR 2 Caucasian intron3 c.248-10A>G Splicing 1 N Novel ABSENT

3 Caucasian intron 3 c.248-10A>G " 3 Y Novel ABSENT

4 Samoan c.283G>A p.Gly 95Arg Missense 4 Y Novel ABSENT

5 Caucasian exon6 c.597T>G p.(Tyr199Ter) Nonsense 6 Y Novel ABSENT

6 Caucasian intron6 c.619+5G>A splice site disruption Splicing 5 Y Reported ABSENT

7 Caucasian intron6 c.619+5G>A " " 1 N " "

8 Caucasian intron 6 c.619+5G>A " " 4 Y " "

9 Chinese 8 c.785C>G p.(Ala262Gly) Missense 2 N reported 1

?VUS/benign 0.00119

10 Indian exon8 c.934G>C p.(Asp312His), Splicing error, exon

8 skipped 3 Y

? Novel reported 2 934G>T and

G>A

ABSENT

11 Indian exon10 c.1234C>T p.(Arg412Ter) nonsense 2 Y reported 3 ABSENT

12 Maori exon 10 c.1236_1239delAAGA p(Glu414GlyfsTer10) deletion,

terminating 5 Y Novel ABSENT

13 Caucasian exon 11 c.1379delT p.(Leu460TyrfsTer16) deletion,

terminating 2 Y Novel ABSENT

14 Caucasian exon14 c.1587delT p.(Ile529MetsfsTer4) deletion,

terminating 1 N Novel ABSENT

15 Caucasian ORF15 c.2236_2237delGA, p.(Glu746fsTer23) del 3 Y reported

3,4,5,6,7,8 ABSENT

16 Caucasian ORF15 c.2305G>T p.(Glu769Ter) Missense 2 N reported 9,10 ABSENT

17 Caucasian ORF15 c.2442_2445delAGAG Deletion 3 Y reported, 3,4,5

18 Maori ORF15 c.2630delA Deletion 18 Novel ABSENT

del.2541-2561 p.Glu848_Gly854del Deletion Y reported 3,4

19 Caucasian ORF15 c.2730_2731delGG p.Gly910fs Deletion 2 Y reported 4

Table 1: XLRP Pathogenic Variants identified in RPGR and RP2

Reference RPGR 1. Buraczynska 1997 2. Sharon 2003 3. Bader 2003 4. Vervoot 2000 5. Breuer 2002

6. Rozet 2002 7. Chung 2003 8 Li 2005

9. Pelletier 2007 10. Kaplan 2007

Gene Ethnicity Molecular Diagnosis Protein prediction Effect # family

members Segregation Novel GnomAD

CHM 1 Caucasian c.49+2dupT p.(?) Duplication 4 Y Ramsden 2013

2 Caucasian c.265A>T p.(Ser89Cys) Missense 1 Y Tarpey 2009 0.013

3 Indian c.525delA Deletion 2 Y novel

4 Caucasian IVS10+1 G>A Missense 6 Y novel

5 Caucasian Ile546 del13aTTCTGTGGGCTCT Deletion 2 Y novel

6 Caucasian del exon7-12 large borders unknown Deletion 2 Y novel

7 Caucasian c.877C>T p.R293* Nonsense 3 Y N

CSNB

CACNA1F 1 Caucasian c.2264C>A p.Ala755Asp Missense 4 Y y

2 Caucasian c.2649_2650insC p.Arg1930His Insertion 6 Y y

3 Māori exon17 c.2234T>C p.Ile745Thr Missense multiple Y Hope 2005* NZ family

4 Caucasian c.868C>T p.Arg290Cys Missense 1 y y

NYX 5 Caucasian exon3 c.425T>G p.Leu142Arg Missense 3 Y Pradhan 2010* NZ Family

XLRS

RS1 1 Caucasian exon1 large deletion, borders unknown Deletion 1 N y

2 Caucasian exon4 c.214G>A p.Glu72Lys Missense 3 Y n

3 Caucasian exon5 c.423_424insC Arg141 ins1cgC Insertion 2 Y y

4 Caucasian exon5 c.329G>A, p.Cys110Tyr Missense 3 Y n

5 Caucasian exon6 c.574C>G p.Pro192Ala Missense 1 N n

6 Caucasian exon6 c.574C>G p.Pro192Ala Missense 1 N n

7 Caucasian exon6 c.? Pro192 ins1 cggC Insertion 2 N n

I:1, ♀ age 69 III:5, ♀ age 23 III:6, ♀ age 18 III:9,♂ age 24

Female affected age 21 XLRP Pedigree #6 RPGRc.619+5G>A

Female affected age 66 XLRP Pedigree #16

RPGRc.2305G>T, p.(Glu769Ter)

Female affected age 74 XLRP Pedigree #9

RPGRc.785C>G, p.(Ala262TGly)

Male affected age 10 XLRP Pedigree #1

RP2c.945_946insT, p.Asn316Ter

Male affected age 41 XLRP Pedigree #12

RPGRc.1236_1239delAAGA

Male affected age 64 XLRP Pedigree #5

RPGRc.597T>C, p.Tyr199Ter

Figure 3. Optos widefield fundus photos and autofluorescence in affected females, Māori and novel genotypes^. Table 2: Pathogenic Variants identified in Choroideraemia, XL Congenital Stationary

Night Blindness, and XL Retinoschisis

Figure 1.Pedigree #16 NZ Māori with ORF15 c.2630delA

Filled square = affected Black = RP

= obligate carrier Red = keratoconus Figure 2. (below) Fundus photos and OCT of affected

individuals from Pedigree #16