Novel RCBTB1 variants causing later-onset non-syndromic retinal dystrophy with macular chorioretinal atrophy

Figures & data

Table 1. Genetic and clinical data

Patient ID / Gender	Variant 1^c	Variant 2^c	Symptoms (onset; y)	Age at exam (y)	Visual acuity	Goldmann perimetry	Electroretinogram
Patient 1^aOGI1042_002062Male	c.358 C > T,p.(Gln120*)	c.1025 C > T,p.(Ser342Leu)	Decreased central vision, glare (42)	46, 49	46y:OD 20/20OS 20/2549y:OD 20/30OS 20/600	Relative central scotomas (≤8° to I4e), otherwise full	Rod-isolated: Reduced amplitude (~50-75% normal)Cone-isolated flicker: Reduced amplitude (30% of normal), normal timing
Patient 2^bOGI3572_005182Female	c.671 C > T,p.(Pro224Leu)	c.1025 C > T,p.(Ser342Leu)	Glare, nyctalopia (47)	49	OD 20/20OS 20/20	Relative central scotomas to I2e only (≤6°); otherwise full	Rod-isolated: Reduced amplitude (~50% normal)Cone-isolated flicker: Normal amplitude and timing
Patient 3OGI3572_005183Male	c.1025 C > T,p.(Ser342Leu)	c.1025 C > T,p.(Ser342Leu)	Decreased central vision (45), nyctalopia (61)	62	OD CF 2 ftOS 20/40	Relative central scotomas (25–35° to I4e), full peripherally	Rod-isolated: Normal amplitude OD, borderline low amplitude OSCone-isolated flicker: Borderline low amplitude with delayed timing OU

^aSegregation analysis confirmed biparental inheritance

^bSegregation analysis not available; gnomAD Variant Co-occurrence calculator used (see text)

^cVariants are based on transcript NM_018191.4

Abbreviations: CF—count fingers; ft—feet; F—female; M—male; OD—right eye; OS—left eye; OU—both eyes; y—years

Table 2. Disease-associated alleles reported to date

Variant^a	gnomAD allele frequency	In silico predictions^b	Protein domain^c	ACMG classification^d	Reference
c.170delG, p.(Gly57Glufs*12)	2.48e-5	Disease causing	RCC1	Pathogenic (PVS1, PM2, PP1-M)	Huang et al (3).; Yang et al (4).
c.358 C > T, p.(Gln120*)	Absent	Disease causing	RCC2	Likely Pathogenic (PVS1, PM2)	Current manuscript
c.671 C > T, p.(Pro224Leu)	1.35e-5	Deleterious; Probably Damaging	RCC4	VUS (PM1, PM2_supporting, PM3_supporting, PP3)	Current manuscript
c.707delA, p.(Asn236Thrfs*11)	1.2e-4	Disease causing	RCC4	Pathogenic (PVS1, PM2, PP1-M)	Huang et al (3).
c.905_906insTT, p.(Gln303Cysfs*17)	Absent	Disease causing	RCC5/6	Likely Pathogenic (PVS1, PM2)	Yang et al (4).
c.919 G > A, p.(Val307Met)	1.2e-5	Deleterious; Probably Damaging	RCC6	Likely Pathogenic (PM1, PM2, PP1-M, PP3)	Coppieters et al (6).
c.930 G > T, p.(Trp310Cys)	7.96e-6	Deleterious; Probably Damaging	RCC6	Likely Pathogenic (PM1, PM2, PP1-M, PP3)	Coppieters et al (6).
c.973 C > T, p.(His325Tyr)	1.42e-4	Tolerated; Possibly Damaging	RCC6	VUS (PM1, PM2, PP1)	Coppieters et al (6).
c.1025 C > T, p.(Ser342Leu)	1.1e-4	Tolerated; Benign	RCC6	Likely Pathogenic (PM1, PM2, PP1-M)	Current manuscript
c.1151A>G, p.(His384Arg)	9.22e-5	Deleterious; Probably Damaging	BTB1	Likely Pathogenic (PM1, PM2, PP1, PP3)	Coppieters et al (6).
c.1164 G > T, p.(Leu388Phe)	Absent	Deleterious; Benign	BTB1	Likely Pathogenic (PM1, PM2, PP1, PP3)	Coppieters et al (6).
c.1202 C > T, p.(Ser401Leu)	3.2e-5	Tolerated; Benign	BTB1	VUS (PM1, PM2, PP1)	Coppieters et al (6).

^aVariants are based on transcript NM_018191.4

^bSIFT and PolyPhen-2 predictions are shown for missense variants; MutationTaster predictions are shown for variants that result in premature protein truncation.

^cRCC: six repeats of RCC1(regulator of chromatin condensation 1)-like domain, BTB:

^dAmerican College of Medical Genetics (ACMG) variant classification (PVS1:null variant; PM1:variant in a functional domain; PM2: extremely rare; PM3: detected in trans with a pathogenic variant; PP1:variant segregates with disease in multiple affected individuals; PP1-M: same as PP1 with multiple families; PP3: multiple lines of computational evidence support a deleterious effect)

Abbreviations: VUS—variant of uncertain significance

Figure 1. Location and features of disease-associated RCBTB1 variants.

The schematic figure shows the location of all the disease-associated variants in RCBTB1 described in the literature and in this report. Novel variants are shown in bold font.

Figure 2. Fundus imaging of patients with RCBTB1-associated retinal dystrophy.

Fundus photography (A-C), fundus autofluorescence (FAF; D-F), and SD-OCT (G-I) were obtained in all patients. In Patient 1, nummular patches of fovea-abutting atrophy were observed on exam and with fundus photography (A). Subtle pigment mottling was present in the midperipheral retina. FAF (D) highlighted the nummular nature of the atrophy and also showed generalized macular hypofluorescence without prominent peripheral disruption. SD-OCT (G) delineated areas of atrophy with a restricted Island of foveal sparing in addition to showing more widespread RPE irregularities.In Patient 2, fundus exam and photography (B) showed fovea-sparing macular atrophy. Fine pigment deposits, nummular areas of chorioretinal atrophy, and occasional larger pigment clumps were present in the peripheral retina. FAF (E) further illustrated the distribution of atrophy and pigment disruption. SD-OCT (H) showed generally intact foveal lamination. Areas of atrophy were also present with associated cystoid spaces and outer retinal tubulations (ORTs).In Patient 3, fundus exam and photography (G) showed extensive macular atrophy with several prominent pigment clumps. Fine pigmentary deposits in the peripheral retina formed a reticular pattern in are``as. FAF (H) showed coalescing nummular hypofluorescence in the macula with narrow strips of preserved signal. Reduced hypofluorescence was present throughout the midperiphery. Extensive chorioretinal atrophy and ORTs were present on SD-OCT (I) with limited areas of preserved outer retinal structure.

Figure 3. Evolution of macular findings in a single patient with RCBTB1-associated retinal dystrophy.

Progressive macular disease was seen over a 3 year interval in Patient 1 as evaluated in near-infrared (A,B), fundus autofluorescence (C,D), and SD-OCT (E,F) imaging, presented for the right eye.

Mabuchi H, Fujii H, Calin G, Alder H, Negrini M, Rassenti L, Kipps TJ, Bullrich F, Croce CM.Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia. Cancer Res. 2001;61(7):2870–77.

 PubMed Web of Science ®Google Scholar

Zhou X, Munger K.Clld7, a candidate tumor suppressor on chromosome 13q14, regulates pathways of DNA damage/repair and apoptosis. Cancer Res. 2010;70(22):9434–43.doi:https://doi.org/10.1158/0008-5472.CAN-10-1960.

 PubMed Web of Science ®Google Scholar

Plafker KS, Singer JD, Plafker SM.The ubiquitin conjugating enzyme, UbcM2, engages in novel interactions with components of cullin-3 based E3 ligases. Biochemistry. 2009;48(15):3527–37.doi:https://doi.org/10.1021/bi801971m.

 PubMed Web of Science ®Google Scholar