L eber congenital amaurosis (LCA) and early -onset severe retinal dystrophy (EOSRD) are part of a group of monogenic inherited retinal dystrophies (IRDs) associated with early vision loss. ^, Severe visual impairment is usually noticed at birth—in the first year of life in LCA and in the first 5 years of life for patients with EOSRD. ^, The estimated prevalence of LCA is 2 to 3 per 100 000 births, representing approximately 5% of all IRDs. Damaging variants generally occur in genes responsible for photoreceptor function or structure, leading to eventual death of outer retinal cells. Clinically, it is suspected in a young child with decreased vision, nystagmus, and rotary eye movements. Although the majority of people with LCA have non-syndromic disease that only affects the retina, a subset have syndromic disease, including experiencing olfactory, auditory, cardiac, renal, or hepatic dysfunction.

Clinical diagnosis of LCA can be supported by electroretinography (ERG) and retinal imaging, including optical coherence tomography (OCT) and fundus imaging at different wavelengths. Typical changes include (1) reduced to non-detectable ERG responses; (2) changes to fundus appearance ranging from maculopathy to generalized retinal dystrophy; and (3) decreased autofluorescence and disrupted outer retinal layers. An important part of the diagnosis is genetic testing. To date, variants in 25 genes have been found in individuals with LCA ( https://retnet.org/ , accessed September 2024), 22 of which are inherited in an autosomal recessive manner. The most common genes associated with LCA include CEP290, CRB1, GUCY2D, RDH12, RPE65, and RPGRIP1 . ^, There have been comprehensive studies analyzing the disease natural history and genotype-phenotype correlations for the former genes; however, little is known about rarer genes associated with LCA as one of their phenotypic presentations, such as CABP4, ALMS1, KCNJ13 , and OTX2 . An approved gene therapy is available for RPE65 -associated retinal dystrophy, whereas promising results, which have resulted in approvals being sought, have been presented for arguably the most severe LCA that is associated with AIPL1 .

CABP4 is involved in the synaptic regulation of calcium influx and neurotransmitter release in photoreceptor synaptic terminals. Variants in this gene are also associated with autosomal recessive congenital stationary night blindness (CSNB). ALMS1 codes for a protein involved in basal body and centromere-associated proteins found in ciliated cells. Pathogenic variants in this gene are associated with Alstrom syndrome; however, it can also rarely present as an isolated retinal dystrophy. ^, KCNJ13 encodes an ion pore that allows potassium to enter into cells. When affected, vitreoretinal degeneration occurs, possibly through impaired phagocytosis repair of the photoreceptor outer segment. OTX2 codes a transcription factor involved in brain, craniofacial, and sensory organ development. Variants in this gene commonly cause syndromic microphthalmia and may be combined with pituitary hormone deficiency.

Double null variants in CABP4 were reported in a family in whom patients had flat ERG, nystagmus, congenital poor vision, minimal fundus changes, and normal night vision. The authors proposed that given the normal fundus appearance, the condition should not be named LCA, but “congenital cone-rod synaptic disorder.” ^, Double null variants in ALMS1 have been associated with LCA and early-onset cone-rod dystrophy in Indian and Chinese patients. ^, Some patients presented with isolated disease, whereas others were subsequently found to have mild uncommon features of Alstrom syndrome that developed through childhood and adolescence (acanthosis nigricans, heart disease, diabetes mellitus). For KCNJ13 , both missense and null variants have been seen in individuals with LCA, characterized by large pigment clumps in the posterior pole and peripapillary region. ^, OTX2 -related cases of LCA are rare, and mostly relate to the regulatory function OTX2 has over CRX. ^, They can appear isolated or combined with microphthalmia, coloboma, or optic nerve hypoplasia.

In this report, we characterize individuals with LCA secondary to damaging variants in the above four rare genes in detail.

RESULTS

Nineteen patients with LCA/EOSRD were included in this cohort and ascertained for phenotyping ( Table 1 ). Seven patients had pathogenic/likely pathogenic variants in CABP4 , 6 in ALMS1 , 3 in KCNJ13 , and 3 in OTX2 ( Table 2 ).

• 
  

  1) CABP4

Table 1

Clinical Characteristics of Patients With Leber Congenital Amaurosis Associated With ALMS1, CABP4, KCNJ13 , and OTX2

Characteristic	ALMS1 (n = 6)	CABP4 (n = 7)	KCNJ13 (n = 3)	OTX2 (n = 3)
Age at baseline, y, mean ± SD	9.8 ± 11.5	19.1 ± 15.8	26 ± 5.0	13.7 ± 9.7
Age at follow-up, y, mean ± SD	22.5 ± 12.7	23.4 ± 17.6	43 ± 1.7	46 ± 26.7
Gender, n (%)
Male	3 (50)	3 (43)	3 (100)	2 (66)
Female	3 (50)	4 (57)	0	1 (33)
Age of onset, y, mean ± SD	1.3 ± 1.3	0.6 ± 0.4	1 ± 0.8	4.7 ± 5.9
Infancy (birth to 2 y)	5 (83)	7 (100)	3 (100)	2 (67)
Childhood (3-11 y)	1 (17)	0	0	0
Adolescence (12-16 y)	0	0	0	1 (33)
Adulthood (>16 y)	0	0	0	0
Baseline BCVA, logMAR, mean ± SD (OD and OS)	1.2 ± 0.8	1.3 ± 0.3	1.7 ± 0.3 OD, 1.9 ± 0.1 OS	1.0 ± 0.4 OD, 1.7 ± 1.1 OS
Final BCVA, logMAR, mean ± SD (OD and OS)	2.2 ± 0.9	1.7 ± 0.6	2.3 ± 0.5	1.6 ± 0.9
Average annual loss of BCVA, logMAR	0.08	0.09	0.03	0.02
Baseline World Health Organization visual impairment category, n (%)
No or mild impairment	1 (17)	0	0	0
Moderate impairment	2 (33)	2 (29)	0	1 (33)
Severe impairment	0	3 (43)	1 (33)	1 (33)
Blindness	3 (50)	2 (29)	2 (67)	1 (33)
Presenting symptoms, n (%)
Photophobia	6 (100)	5 (71)	0	0
Nystagmus	5 (83)	7 (100)	1 (33)	1 (33)
Nyctalopia	0	0	3 (100)	2 (66)
Poor vision	4 (67)	5 (71)	3 (100)	3 (100)

 

BCVA = best-corrected visual acuity, y = years.

Table 2

Variants Within the Cohort of Patients With Leber Congenital Amaurosis Associated With Less Common Genes

Gene	Variant c.	Amino Acid Change	ACMG Classification						Allele Frequency (gnomAD)					Functional Prediction							ClinVar ID	Comment
			Verdict	Criteria										REVEL			MutationTaster		Conser vation	SpliceAI
				Factor 1	Factor 2	Factor 3	Factor 4	Factor 5	Allele n°	Latino	African	Asian	Euro pean (Non- Finnish)	Total	Predi ction	Rank score	Predi ction	Score	PhyloP 100wa y
ALMS1	c.9001C>T	p.Gln3001 *	Likely pathogenic	PVS1	PM2	PP5			13	Absent	Absent	Absent	0.000 0117	8.89E-06	NA	NA	Uncer tain	1	0.317	NA	1457897	1X Patho genic
	*c.284del	p.Pro95Argfs *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	0.19	Benign (0)	NA
	c.10483C>T	p.Gln3495 *	Likely pathogenic	PVS1	PM2	PP5			99	Absent	Absent	Absent	8.83 E-05	6.79 E-05	NA	NA	Unce rtain	1	2.231	NA	210 122	9X Patho genic
	*c.2822T>A	p.Leu941 *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	Unce rtain	1	0.241	NA	NA
	*c.4568dup	p.Tyr1523 *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	0.42	Benign (0)	NA
	*c.2958_ 2959ins CTATTC TGGACTG	p.Thr987Leufs *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	-0.226	NA	NA
	*c.4148C>G	p.Ser1383X *	Likely pathogenic	PVS1	PM2				1	Absent	Absent	Absent	8.99 E-07	6.84 E-07	NA	NA	Delet erious	1	0.225	Benign (0)	NA
	c.1793del	p.Glu598Glyfs *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	-1.075	NA	NA
	*c.6590del	p.Lys2197Serfs *	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	Delet erious	1	0.93	NA	NA
	c.10972C>T	p.Arg3658 *	Likely pathogenic	PVS1	PM2	PP5			26	Absent	Absent	Absent	0.000 0216	0.000 0178	NA	NA	Unce rtain	1	1.32	NA	977 960	3X Patho genic
	c.10775del	p.Thr3592Lysfs *	Likely pathogenic	PM1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	Delet erious	0.91	Delet erious	1	0.932	Benign (0.03)	NA
CABP4	g.67226212- 67226422	NA	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	8.53	NA
	c.673C>T	p.Arg225Ter	Pathogenic	PVS1	PM2	PP5			14	0.000 0224	0.000 0299	Absent	0.000 0108	9.59 E-06	NA	NA	Delet erious	1	-0.384	Benign (0.02)	438047	4X Patho genic, 1X Likely pathogenic
KCNJ13	c.496C>T	p.Arg166Ter	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	Bening	0.26	Delet erious	1	2.453	Benign (0.03)	30331	2X Path ogenic
	c.722T>C	p.Leu241Pro	Likely pathogenic	PM2	PM3	PP3	PP5		1	Absent	Absent	Absent	Absent	6.84 E-07	Delet erious	0.94	Delet erious	1	9.29	Benign (0.01)	30332	1X Path ogenic
OTX2	*c.819del	p.Trp274Glyfs*28	Likely pathogenic	PVS1	PM2				Absent	Absent	Absent	Absent	Absent	Absent	NA	NA	NA	NA	9.76	Benign (0)	NA
	*c.271C>A	p.Gln91Lys	Likely pathogenic	PM2	PM5	PP2	PP3		Absent	Absent	Absent	Absent	Absent	Absent	Delet erious	0.78	Delet erious	1	9.985	Benign (0)	NA
	*c.235G>C	p.Glu79Gln	Likely pathogenic	PM2	PM5	PP2	PP3		Absent	Absent	Absent	Absent	Absent	Absent	Delet erious	0.83	Delet erious	1	7.892	Benign (0)	NA

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