Case: Family 11 GC21390 Proband II:1, 49yo at onset (incidental finding), 56yo at report

CasePresentingHPOs:

CasePresentingHPOsFreeText: Prolonged dark adaptation, peripheral visual field loss, BCVA= 6/9, 6/5, retinitis pigmentosa, hypertension, plasma coQ10 level=582.28nmol/L (Reference range: 227- 1432 nmol/L)

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: negative IRD gene panel analysis

CaseGenotypingMethod: genome sequencing, direct Sanger

Variant: c.933delC p.(Tyr311); c.682-7 T > G p.(Gln230); p.(Leu193Phefs*27)

ClinVarID: or CAID: CA6828694; CA6828747

gnomAD: This nonsense variant, Tyr311Ter in exon 7/7, is present in gnomAD v4.1.0 with a MAF=0.00002627 (31/1179996 alleles) in the European NF population with 0 homozygotes. The score has been reduced since NMD is not expected to occur.

This non-canonical splice site variant, c.682-7T>G, is present in gnomAD v4.1.0 with a MAF=0.001031 (66/64040 alleles) in the European Finnish population with 0 homozygotes.

AddCaseInfo: only family member noted to be affected, mother was unaffected and heterozygous for tyr311ter but father is deceased and not genotyped

PreviouslyPublished: n/a

VariantEvidence: RT-PCR of patient blood derived mRNA using oligonucleotide primers targeting COQ5 (Supplementary Table 6) followed by agarose gel electrophoresis showed definite altered transcript length and mis-splicing for the COQ5 c.682-7 T > G variant. ONT sequencing of the full COQ5 transcript from whole blood of individual family 11, II:1 showed skipping of exon 5 to be the predominant effect of the c.682-7 T > G variant leading to early termination and probable nonsense-mediated decay (p.(Gln230)) (Fig. ​(Fig.4).4). In addition, exon 4–5 skipping was identified in a low proportion of reads (3%) leading to a reading-frame shift and early termination (p.(Leu193Phefs27)).

Case: Family 12 Proband, 5yo at onset, 38yo at report

CasePresentingHPOs:

CasePresentingHPOsFreeText: Muscle weakness (hyposthenia), followed by vision problems in the dark (14), BCVA=6/18, 6/7.5, retinitis pigmentosa, nystagmus, infantile appearance, hypertelorism, undeveloped fertile function, constricted visual field

CaseNOTHPOs:

CaseNOTHPOSFreeText:

CasePreviousTesting: negative IRD gene panel analysis

CaseGenotypingMethod: "genome-wide analysis" -exome or genome sequencing

Variant: c.367 C > T p.(Arg123Trp); c.682-7 T > G p.(Gln230); p.(Leu193Phefs27)

ClinVarID: or CAID: CA6828832; CA6828747

gnomAD: This non-canonical splice site variant, c.682-7T>G, is present in gnomAD v4.1.0 with a MAF=0.001031 (66/64040 alleles) in the European Finnish population with 0 homozygotes.

This missense variant, p.Arg123Trp, is present in gnomAD v4.1.0 with a MAF=0.00002665 (2/75052 alleles) in the African/African American population and 0 homozygotes.

AddCaseInfo: only family member noted to be affected, others do not have genotype information available

PreviouslyPublished: n/a

VariantEvidence: