Feedback of results. Report via to NTGMC inbox. Review by GMC clinician

Transcription

1 Genetic deafness Maria Bitner-Glindzicz Genetics and Genomic Medicine Programme UCL Institute of Child Health, UCL Ear Institute, and Great Ormond Street Hospital for Children

2 Feedback of results Report via to NTGMC inbox Review by GMC clinician Preliminary report and discussion with referring Clinician to schedule patient for MDT Referring clinician, genetics team & clinical scientists review MDT virtual or face-to-face Potential variant No potential variant Validation Inform referring clinician who lets patient know report to referring clinician NT GMC Referring clinician sees patient +/-clinical genetics if needed Copy of report to Genomics England

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6 Genomics MDM record Referring clinician: Maria Bitner- Gindzicz Referring department: Clinical Genetics, GOSH Forename: Click to enter text Surname: Click to enter text DOB: NHS no: Click to enter text GOSH hosp no: Click to enter text Family ID: Phenotype summary: Bilateral microtia, cleft palate, feeding difficulties Source of variant data: GOSH diagnostic lab Other diagnostic lab Research lab Lab / research study name: 100,000 Genomes Pilot Details and method(s): Trio genome Variant classification and interpretation: Variant 1 (HGVS nomenclature): SIX1 c.517a>c p.lys173gln de novo MDM decision: Variant class Class 4 Phenotype contribution Partial Variant 2 (HGVS nomenclature): CDT1 c.248c>t p.pro83leu MDM decision: Variant class Class 2 Phenotype contribution None Variant 3 (HGVS nomenclature): CDT1 c.412c>t p.arg138trp MDM decision: Variant class Class 3 Phenotype contribution None Variant 4 (HGVS nomenclature): CDT1 c.1367a>c p.glu456ala MDM decision: Variant class Class 2 Phenotype contribution None Comment: SIX1: fits with the phenotype though no renal phenoytpe. This variant is adjacent to one of the previously identified missenses. Uncertainty whether this fully explains the phenotype (feeding difficulties requiring fundoplication and gastrostomy) CDT1: phenotype doesn t fit; compound het and none of the variants are convincingly pathogenic Action: Lab to confirm SIX1 findings. MBG to consider renal ultrasound scan.

7 Deafness gene panel

8 ACTG1 ATP2B2 BDP1 CABP2 CCDC50 CDH23 CEACAM16 CIB2 CLDN14 CLPP CLRN1 COCH COL11A2 COL4A6 CRYM DFNA5 DFNB31 DFNB59 DIABLO DIAPH1 DIAPH3 EDN3 EDNRB ESPN ESRRB EYA1 EYA4 GIPC3 GJB2 GJB3 GJB6 GPR98 GPSM2 GRHL2 GRXCR1 HARS HARS2 HGF HSD17 ILDR1 KARS KCNJ1 KCNQ KIT LARS2 LHFPL LOXH LRTOMT MARVELD2 MIR96 MITF MSRB3 MYH14 MYH9 MYO15A MYO3A MYO6 MYO7A OSBPL2 OTOA OTOF OTOG P2RX2 PAX3 PCDH15 PDZD7 PNPT1 POU3F4 POU4F3 PRPS1 PTPRQ RDX RPGR SERPINB6 SIX1 SIX5 SLC17A8 SLC4A11 SMPX SNAI2 SOX10 STRC TECTA TJP2 TMC1 TMIE TMPRSS3 TPRN TRIOBP USH1C USH1G USH2A WFS1

9 New additions GATA3 KCNE1 KCNQ1 OSBPL2 OTOGL SYNE4 TBC1D2 TNC TSPEA CD164 CLIC5 EPS8 S1PR2 NARS2

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11 GJB2:c.383insTCCGCAT (ins7bp) ins7bp/n

12 N/N ins7bp/n GJB2:c.383insTCCGCAT (ins7bp) ins7bp/n

13 ins7bp/n N/N ins7bp/n ins7bp/n GJB2:c.383insTCCGCAT (ins7bp) ins7bp/n

14 ins7bp/n N/N ins7bp/n ins7bp/n N/N GJB2:c.383insTCCGCAT (ins7bp) ins7bp/n N/N ins7bp/ins7bp

15 Deafness gene panel test

16 GPSM2 c a>c homozygous

17 GJB2:c.383insTCCGCAT (ins7bp) ins7bp/n N/N ins7bp/n ins7bp/n GPSM2:c A>C ins7bp/n GPSM2:c A>C ins7bp/ins7bp

18 Chudley McCullough syndrome GPSM2 mutations (G protein signalling modulator 2) Orienting mitotic spindles; establishment of polarity during cellular differentiation Recessive Bilateral sensorineural HL and hydrocephalus due to foramen of Munro obstruction (and dilatation of lateral ventricles). Mennonite families. Phenotypically normal Callosal dysgenesis, grey matter heterotopia, cerebellar dysgenesis, arachnoid cysts

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21 Misorientation of hair bundle; malformations of stereocilia Bhonker et al, Mamm Genome 2016

22 Congenital profound Mild/moderate hearing loss in 30 s Perforated ear drum

23 Younger sibling Failed NHSP Profound hearing loss Sat 13m Walked 18m+ Bilateral CI, doing well Older child Failed NHSP Profound hearing loss Not sitting unsupported at 8m Head control at 5-6m ECG and ERG requested 2012, No further testing but things may change in next few years

24 Congenital profound Mild/moderate hearing loss in 30 s Perforated ear drum

25 MYO6 MYO6: c heterozygous MYO6: c heterozygous MYO6: c homozygous Congenital profound MYO6: c homozygous Mild/moderate hearing loss in 30 s Perforated ear drum

26 Brownstein et al 2013, EJHG

27 MYO6 Can cause autosomal dominant post-lingual hearing loss often manifesting in 30 s (DFNA22) Can also cause recessively inherited congenital profound hearing loss (DFNB37) Possibly some semi-dominant mutations

28 Failed NHSP Profound deafness Motor delay Vestibular hypofunction MYO6: c.1729_1741del hom p.(phe577ilefs*28) DIAPH1:c T>C het

29 MYO6: c.1729_1741del MYO6: c.1729_1741del DIAPH1:c T>C het Failed NHSP Profound deafness Motor delay Vestibular hypofunction MYO6: c.1729_1741del DIAPH1:c T>C het Relevance of heterozygous LOF mutation in DIAPH1??

30 MYO6 20 s 20 s Adult onset hearing loss, 30 s Congenital profound hearing loss

31 Congenital moderate hearing loss Failed NHSP m.1555a>g

32 Congenital moderate hearing loss Adult onset, moderate HL m.1555a>g m.1555a>g Possibly fits with phenotype

33 Congenital moderate hearing loss m.1555a>g m.1555a>g But added information that Dad has profound congenital deafness!

34 MYO6: c.187+2t>c MYO6: c.187+2t>c m.1555a>g MYO6: c.187+2t>c m.1555a>g But why is Dad more severely affected??

35 MYO6: c.187+2t>c MYO6: c.187+2t>c m.1555a>g MYO6: c.187+2t>c m.1555a>g STRC c.3176t>c p.(leu1059pro) and c.5276c>t p.(arg1759*) in Dad

36 But there is a pseudogene..so origin and location of variants is currently uncertain

37 *STRC c.3176t>c p.(leu1059pro) ; c.5276c>t p.(arg1759*) MYO6: c.187+2t>c MYO6: c.187+2t>c *STRC.. m.1555a>g MYO6: c.187+2t>c m.1555a>g STRC variants are in cis as both are present in paternal grandfather Watch this space..

38 Acknowledgements Thomas Cullup, Lucy Jenkins, Ann-Marie Differ, Cathy Meaney, Suzy Drury, Emma Ashton GOSgene team, Hywell Williams, Chiara Bacchelli, Janice Lee, Polona Le Quesne Stabej Robert Kleta, Horia Stanescu Alistair Calder All clinical colleagues at GOSH and RNTNEH