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. 2025 Apr 17;10:32. doi: 10.1038/s41525-025-00489-1

Variants in CFAP410 cause a range of retinal and skeletal phenotypes

Ryan E Schmidt 1, Amy E Pohodich 1, David Birch 2, Kaylie Jones 2, Byron L Lam 3, Emily H Jung 4, Nieraj Jain 5, Michalis Georgiou 6,7, Omar A Mahroo 6,7, Andrew R Webster 6,7, Michel Michaelides 6,7, Benjamin Bakall 8,9, Alessandro Iannaccone 10,11,12, Ajoy Vincent 13, Deepika C Parameswarappa 13, Elise Heon 13, Hendrik P N Scholl 14,15, Lucas Janeschitz-Kriegl 14,15, Elias I Traboulsi 16, Wadih Zein 17, Brian P Brooks 17, Catherine Cukras 17, Robert Hufnagel 17, Tomas S Aleman 18, Mohamed M Sylla 19, Stephen H Tsang 19, Michelle Alabek 20, Jose Sahel 20, Michael B Gorin 21, Maria M van Genderen 22,23, Katarina Stingl 24, Milda Reith 24, Susanne Kohl 24, Rebeca Azevedo Souza Amaral 25, Juliana Maria Ferraz Sallum 25, Andrea L Vincent 26,27, Sarah Hull 26,27, Jacque L Duncan 28, James V M Hanson 29, Matthias Tedeus 30, Jordi Maggi 31, Urs Graf 31, Samuel Koller 31, Wolfgang Berger 31,32,33, Christina Gerth-Kahlert 29, Molly Marra 1, Lesley A Everett 1, Paul Yang 1, Mark E Pennesi 1,2,✉
PMCID: PMC12006490  PMID: 40246852

Abstract

Ciliopathies are associated with a range of phenotypes including retinal degeneration and skeletal abnormalities. We present a retrospective study of 49 patients with variants in Cilia and Flagella Associated Protein 410 (CFAP410) from multiple ophthalmic centers across the world. Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation. A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy. A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX). Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410, and the structural effects of these variants were modelled using ChimeraX. This report furthers our understanding of CFAP410-associated clinical phenotypes such as retinal dystrophy and skeletal dysplasia.

Subject terms: Molecular medicine, Disease genetics, Medical genetics

Introduction

Ciliopathies are a diverse group of disorders that result from the functional disruption of proteins responsible for assembling and maintaining cilia1. Patients with ciliopathies can present with a range of systemic findings including kidney disease, central nervous system disorders, skeletal abnormalities, and retinal dysfunction1. Disease-associated variants within Cilia and Flagella Associated Protein 410 (CFAP410, also known as C21orf2, OMIM *603191) have been implicated in the pathogenesis of an autosomal recessive retinal dystrophy associated with spondylometaphyseal dysplasia2,3.

The protein encoded by CFAP410 is 256 residues long, rich in leucine residues, and involved in ciliogenesis and the maintenance of cilia in photoreceptor cells of the retina4–7. The leucine-rich-repeat region (LRR, Fig. 1 top panel) of CFAP410 is highly conserved and essential for interacting with the negatively charged “C21orf2 interaction domain (CID)” at the C-terminus of NEK1 (NIMA related kinase 1, Supplementary Fig. 1)5. Another highly conserved region of CFAP410 is the leucine-rich repeat C-terminal region (LRRCT, Fig. 1 bottom panel), which provides structural integrity by shielding internally facing hydrophobic residues8–12. Sequence variations within both the LRR and LRRCT have recently been found to be pathogenic in patients with retinal dystrophy and skeletal abnormalities13–18.

Fig. 1. Wild type CFAP410 protein.

Fig. 1

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A The Leucine Rich Repeat region (residues 19-84) is highlighted in red. Image generated by ChimeraX20. B The LRRCT (Leucine Rich Repeat C-Terminal region) highlighted in red. Image generated by ChimeraX20.

The most widely identified phenotypes of CFAP410 disease-associated variants are retinal dystrophy with macular staphyloma (OMIM #617547), and axial spondylometaphyseal dysplasia (SMDAX, OMIM #602271). The link between CFAP410 variants and retinal dysfunction in vivo was first established by Abu-Safieh et al., who used whole exome sequencing to identify a single base pair deletion in CFAP410 in a patient with cone-rod dystrophy (CORD) but no reported skeletal abnormalities2. Wang et al. identified CFAP410 as the genetic cause of SMDAX, a ciliopathy with skeletal abnormalities including short stature with a small thorax, anterior rib cupping, proximal femoral dysplasia, and lacy iliac crests6,7. In addition to SMDAX and retinal dystrophy, variants in CFAP410 have been associated with Amyotrophic Lateral Sclerosis (ALS)19.

The clinical presentation of reported patients with biallelic CFAP410 variants is highly variable, with a large phenotypic range of skeletal involvement and retinal dysfunction. While the skeletal phenotype has been more frequently reported, it is unclear if the lower frequency of patients described with a retinal phenotype is the result of milder or absent expression of this phenotype. We collected data from 49 patients with CFAP410 disease-associated variants in a multi-center study involving ophthalmic genetics centers worldwide to comprehensively characterize the spectrum of ophthalmologic and systemic features of this rare disorder.

Results

Demographic findings

Forty-nine patients with conclusive molecular genetic testing from 42 families were identified with CFAP410-associated retinal dystrophy (Table 1). The study population included 20 males and 29 females. Age at first ophthalmology visit ranged from 4 to 69 years (mean 25.8 years, median 25.0 years). Ages at most recent exam with ophthalmic imaging ranged from 4 to 69 years (average 32.1 years; median 28 years). Age of onset of visual symptoms ranged from <1 month to 50 years (average 11.4 years, median 6.0 years).

Table 1.

Ophthalmic features of patients with CFAP410-associated retinal dystrophy

Patient ID Variant 1 (Testing) (Segregation) Variant 2 (Segregation) Initial BCVA (OD; OS) (Age in yr) Recent BCVA (OD; OS) (Age in yr) Ocular Signs and Symptoms Anterior Segment Macula Peripheral Retina
1 p.Arg73Pro (WES) (maternal) p.Leu23Pro 20/125; 20/125 (47) 20/800; 20/320 (62) Decreased acuity; prolonged light/dark adaptation; nyctalopia; nystagmus; impaired color vision; photophobia Cataract OU Macular atrophy Chorioretinal atrophy with pigment redistribution
2 p.Pro116Leu (WES) p.Leu224dup 20/25; 20/20 (50) 20/32; 20/32 (62) Decreased acuity; prolonged light/dark adaptation; nyctalopia; impaired color vision; field constriction Cataract OU Atrophy of Macula and RPE Bone spicules; peripheral atrophy; vascular attenuation
3 p.Arg73Pro (WES) p.Arg70Gln 20/100; 20/70 (42) 20/200; 20/400 (56) Decreased acuity; photophobia Cataract OU; corneal guttae OU; ABMD OU Macular schisis with lamellar hole OS; retinoschisis; ERM; CMD Posterior staphyloma OU; reticular degeneration
4 p.Glu128-ValfsTer3 (WES) p.Glu96-ProfsTer42 20/100; 20/80 (28) No follow-up Decreased acuity; photophobia; prolonged light/dark adaptation; photopsia Unremarkable Blunted foveal reflex, tessellated posterior pole OU Unremarkable
5 p.Glu96-ProfsTer42 (WES) (maternal) p.Glu128-ValfsTer3 20/50; 20/50 (25) No follow-up Decreased acuity; photophobia Unremarkable Blunted foveal reflex, tessellated posterior pole OU Unremarkable
6 p.Arg73Pro (WES) p.Arg73Pro 20/30; 20/25 (19) 20/30; 20/25 (24) Decreased acuity; photophobia; prolonged light/dark adaptation; nyctalopia Unremarkable Blunted foveal reflex; foveal granularity OU Hypopigmentation; vascular attenuation; inferior and temporal pigmentary changes
7 p.Arg73Pro (WES) p.Arg73Pro 20/50; 20/50 (25) 20/50; 20/50 (29) Decreased acuity; prolonged light/dark adaptation; nyctalopia Unremarkable Blunted foveal reflex; ERM Hypopigmentation; vascular attenuation
8 c.96+1G>A (NGS) c.96+1G>A Not reported No follow-up Decreased Acuity Not reported Macular atrophy; nerve fiber pigment Not reported
9 p.Arg73Pro (NGS) (paternal) p.Thr46Met (maternal) 20/50; 20/63 (16) 20/100; 20/63 (30) Decreased acuity; prolonged light/dark adaptation; nyctalopia; impaired color vision; photophobia; photopsia Unremarkable Absent foveal reflex, pale optic nerve head Bone spicules; attenuated vessels
10 p.Glu96Lys p.Glu96Lys 20/70; 20/60 (31) 20/60; 20/60 (33) Decreased acuity; nystagmus; prolonged light/dark adaptation; impaired color vision Unremarkable Peripapillary atrophy, tilted optic nerve head Lattice degeneration
11 c.96+1G>A (NGS) c.96+1G>A Not reported No follow-up Decreased acuity Unremarkable Atrophy of macula and RPE; pigment between arcades Unremarkable
12 p.Arg73Pro (NGS) p.Arg73Pro 20/100; 20/125 (54) No follow-up Decreased acuity Cataract OU Macular atrophy Unremarkable
13 p.Arg73Pro (NGS) p.Arg73Pro HM; HM (43) HM; 20/800 (45) Decreased acuity Unremarkable Macular atrophy Bone spicules
14 p.Arg73Pro (NGS) c.96+6T>A 20/40; 20/40 (28) 20/125; 20/160 (43) Decreased acuity; nyctalopia Cataract OU Macular Atrophy, pale optic nerve head Atrophy; pigmentary changes
15 p.Arg73Pro (NGS) p.Pro98Leu 20/40; 20/40 (28) No follow-up Decreased acuity; photophobia; nyctalopia Unremarkable Unremarkable Bone spicules
16 p.Val20AlafsTer24 (NGS) p.Glu148GlyfsTer21 20/200; 20/200 (21) No follow-up Decreased acuity; photophobia; nystagmus Unremarkable Unremarkable Atrophy; pigmentary changes
17 p.Glu96Lys (NGS) p.Glu96Lys 20/60; 20/60 (35) 20/120; 20/80 (53) Decreased acuity; photophobia; Unremarkable Blunted foveal reflex Atrophy of far periphery
18 p.Arg73Pro (NGS) p.Arg73Pro 20/60; 20/60 (10) 20/60; 20/60 (18) Decreased acuity Unremarkable Blunted foveal reflex, mottling Unremarkable
19 p.Glu96Lys (NGS) p.Glu96Lys 20/40; 20/50 (35) No follow-up Decreased acuity; nyctalopia Unremarkable Unremarkable Atrophy inferiorly and nasally
20 p.Val20Met (NGS) p.Val20Met 20/60; 20/40 (32) 20/50; 20/50 (36) Decreased acuity; prolonged light/dark adaptation; nyctalopia; impaired color vision; photophobia Unremarkable Blunted foveal reflex Atrophy inferiorly
21 p.Ile33LeufsTer33 (NGS) p.Ile33LeufsTer33 20/60; 20/80 (25) 20/60; 20/60 (34) Decreased acuity; impaired color vision; photophobia Alternating esotropia Unremarkable Atrophy
22 p.Ala12-SerfsTer60 (NGS) p.Arg73Pro 20/120; 20/120 (6) No follow-up Decreased acuity; nyctalopia; impaired color vision Cataract OU Pigment mottling Atrophy
23 p.Arg90Pro (NGS) p.Ala12SerfsTer60 20/200; LP (46) NLP; NLP (53) Decreased acuity; photophobia; nystagmus; impaired color vision Cataract OU Pigment mottling, waxy pallor of optic nerve head Atrophy
24 p.Pro116Leu (WES) (maternal) p.Thr114-Arg117dup (paternal) 20/80; 20/63 (8) 20/63; 20/63 (12) Decreased acuity Unremarkable Xanthophyllic Midperipheral pigmentary change
25 p.Gln119Ter (WES) (paternal) p.Leu23Pro 20/60; 20/60 (8) 20/63; 20/63 (11) Decreased acuity; photophobia Unremarkable Unremarkable Pigment mottling
26 p.Gly101AlafsTer14 (WES) p.Gly101AlafsTer14 Not reported No follow-up Decreased acuity; nyctalopia, prolonged light/dark adaptation; impaired color vision Not reported Not reported Not reported
27 p.Arg73Pro (WES) p.Arg73Pro LP; CF (69) No follow-up Decreased acuity; photophobia; prolonged light/dark adaptation; impaired color vision; field constriction Cataract OU Macular schisis with lamellar hole OU; posterior staphyloma OU; RPE loss Nummular atrophy; bone spicules
28 p.Arg73Pro (WES) p.Arg73Pro HM; LP (67) No follow-up Decreased acuity Cataract OU Posterior staphyloma OU Nummular RPE atrophy
29 p.Met109AlafsTer10 (NGS) p.Met109AlafsTer10 20/80; 20/80 (8) 20/100; 20/100 (11) Decreased acuity; prolonged light/dark adaptation; nyctalopia Unremarkable Blunted foveal reflex; pigment mottling; hypo-pigmented ring Pigmentary changes
30 p.Arg73Pro (WES) p.Arg73Pro 20/80; 20/80 (3) 20/80; 20/80 (7) Decreased acuity; photophobia; prolonged light/dark adaptation; nystagmus Unremarkable Absent foveal reflex Pigmentary changes
31 p.Arg73Pro (WES) p.Arg73Pro 20/60; 20/60 (4) 20/160; 20/250 (22) Decreased acuity; prolonged light/dark adaptation; nyctalopia; nystagmus; impaired color vision; field constriction Unremarkable Blunted foveal reflex; pigment mottling Pigmentary changes, scattered white flecks
32 p.Arg224delinsLeuArg p.Arg224delinsLeuArg 20/50; 20/50 (8) 20/40; 20/50 (15) Decreased acuity Unremarkable Unremarkable Temporal pigmentary changes; vascular attenuation
33 p.Arg224delinsLeuArg p.Arg224delinsLeuArg 20/60; 20/60 (7) 20/60; 20/40 (17) Decreased acuity; Unremarkable Foveal hypoplasia Pigmentary changes; vascular attenuation
34 p.Arg73Pro (NGS) p.Gly27Val HM; LP (54) LP; NLP (61) Decreased acuity; prolonged light/dark adaptation; nyctalopia; nystagmus; impaired color vision; field constriction Cataract OU RPE atrophy Bone spicules
35 p.Met109AlafsTer10 (NGS) p.Met109AlafsTer10 20/100; 20/100 (9) 20/100; 20/100 (9) Decreased acuity; prolonged light/dark adaptation; nyctalopia; impaired color vision Unremarkable Blunted foveal reflex, attenuated vessels, pale optic nerve head RPE mottling with no bone spicules
36 p.Arg73Pro Deletion of all coding exons LP; HM (65) No follow-up Decreased acuity; prolonged light/dark adaptation; nyctalopia; impaired color vision; photophobia Unremarkable Staphyloma Pigmentary retinopathy
37 p.Cys36Tyr (NGS) p.Cys36Tyr 20/80; 20/70 (NA) No follow-up Decreased acuity; photophobia; prolonged light/dark adaptation; impaired color vision Glaucoma Unremarkable Pigmentary retinopathy
38 c.460_469delGGCCCCAAGC (NGS) p.Arg73Pro 20/50; 20/100 (5) 20/150; 20/150 (15) Decreased acuity Unremarkable Pigment mottling Pigmentary retinopathy; depigmented lesions
39 p.Ala12SerfsTer60 (NGS) (maternal) p.Arg108His (paternal) 20/100; 20/100 (7) No follow-up Decreased acuity Unremarkable Posterior staphyloma OU Pigmentary retinopathy, coloboma
40 p.Val111Met (NGS) p.Val111Met 20/40; 20/60 (47) No follow-up Decreased acuity; photophobia Cataract OU Atrophic macula, pale optic nerve head Atrophy, bone spicules, vascular attenuation
41 p.Val111Met (NGS) (maternal) p.Val111Met (paternal) 20/30; 20/200 (16) 20/400; 20/40 (18) Decreased acuity, photophobia Unremarkable Atrophic macula, pale optic nerve head Bone spicules OD, narrow vessels OU
42 c.-18_23del (start codon loss) (gene panel) c.-18_23del 20/50; 20/50 (12) No follow-up Nyctalopia; light/dark adaptation decreased peripheral vision; impaired color vision; field constriction Unremarkable Blunted foveal reflex Pigmentary retinopathy, attenuated vessels, hypopigmented dots
43 p.Ser136ArgfsTer25 (gene panel) p.Thr114Arg117dup 20/125; 20/125 (6) 20/100; 20/100 (15) Nystagmus; photophobia Unremarkable Sawtooth EZ on OCT Unremarkable
44 p.Arg73Pro (gene panel) p.Ala12SerfsTer60 20/50; 20/125 (4) 20/40; 20/40 (5) Decreased acuity; photophobia Unremarkable Sawtooth EZ on OCT Mottled periphery
45 p.Arg73Pro (WES) p.Arg73Pro NLP; LP (65) No follow-up Decreased acuity; prolonged light/dark adaptation; impaired color vision Cataract OS Staphyloma Nummular peripheral RPE atrophy
46 p.Pro116Leu (NGS) p.Pro116Leu 20/70; 20/80 (14) 20/70; 20/70 (21) Decreased acuity, None Mild pigment mottling Myopic thinning and mottling
47 p.Val20Ala (gene panel) (inherited) c.(77+1_78-1)_(96+1_97-1)del 20/25; 20/25 (44) 20/63; 20/63 (66) Decreased acuity, photophobia Unremarkable Dull macular reflex, pale optic nerve head Atrophy, Inferior pigmentary changes
48 p.Val20Ala (gene panel) (inherited) c.(77+1_78-1)_(96+1_97-1)del 20/100; 20/80 (52) 20/125; 20/100 (60) Decreased acuity, nyctalopia, photophobia Unremarkable Dull macular reflex, pale optic nerve head Atrophy, RPE changes, yellow intraretinal deposits
49 c.-18_23del (gene panel) c.-18_23del 20/32; 20/32 (11) 20/40; 20/40 (13) Decreased acuity, nyctalopia, field constriction Unremarkable Loss of macular reflex, pale optic nerve head Atrophy, yellow dots
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Sibling pairs included patients 4 and 5, 6 and 7, 8 and 11, 12 and 13, 27 and 28, 32 and 33, as well as 47 and 48.

BCVA best corrected visual acuity, HM hand motion, LP light perception, NLP no light perception, EZ ellipsoid zone, RPE retinal pigment epithelium, ABMD anterior basement membrane dystrophy, ERM epiretinal membrane, OCT optical coherence tomography, CMD cystoid macular degeneration.

Molecular findings

A total of 31 CFAP410 variants were identified (Table 1), including 13 missense variants, 12 frameshifting small deletions (including one deletion resulting in start codon loss), 2 in-frame duplications, 2 splicing variants, 1 in-frame insertion, 1 frame-shifting insertion, 1 small indel variant, and 1 nonsense variant. Fourteen of these variants were previously reported, including p.Arg73Pro3,6,14,19, p.Pro116Leu6, p.Val111Met12,20, p.Thr46Met21, p.Glu96Lys22, c.96+6T>A3,23, c.96+1G>A2,3,24,25, p.Arg70Gln26, p.Arg90Pro21, p.Pro98Leu27, p.Ala12SerfsTer6021, p.Val20AlafsTer2427, p.Glu128ValfsTer33, p.Glu148GlyfsTer2127, and p.Thr114_Arg117dup9. Many of these variants map to known functional domains of CFAP4109–12. The most frequent variant was c.218G>C, p.Arg73Pro, which accounted for at least one altered allele in 20 patients (40.8%), as well as 30.6% of all pathogenic alleles (30/98).

Segregation analysis with testing of both parents was successfully performed in patients 9, 24, 39, 41, and 44, segregation analysis of only one parent was performed in patients 1, 5, 25, and 43 (Table 1). Seven patients had a history of familial consanguinity, including five patients whose parents were first degree cousins (patients 11, 20, 37, 48, and 49), and two patients with consanguinity among grandparents (patients 35 and 42). Nineteen patients reported a family history of related eye problems. Sibling pairs included patients 4 and 5, 6 and 7, 8 and 11, 12 and 13, 27 and 28, 32 and 33, as well as 47 and 48.

Ophthalmic findings

Ophthalmic findings for each patient are summarized in Table 1. All patients reported decreased BCVA, and 37 out of 49 patients reported an onset of visual symptoms before age 18. In most cases, measured BCVA worsened over time, but the degree of visual impairment was highly variable (from 20/20 to no light perception). Mean BCVA at each patient’s initial visit was LogMAR 0.81 ± 0.77 and 0.83 ± 0.72 at most recent visit, respectively. Other frequent visual complaints included photophobia (23 patients), prolonged light-to-dark adaptation (21 patients), reduced color vision (20 patients), nyctalopia (20 patients), visual field constriction (10 patients), nystagmus (7 patients), and photopsia2 (Table 1).

Few anterior segment abnormalities were noted. The most common abnormality was cataracts, found in 13 of 49 patients. Seven patients had cataract surgery, and their age at the time of surgery ranged from 36 through 69 years. Cornea guttae, strabismus, and glaucoma were each only found in one individual patient (Table 1).

Commonly reported abnormalities of the macula included pigmentary changes (24 patients), blunted or loss of foveal reflexes (16 patients), and atrophy of the macula or retinal pigment epithelium (15 patients) (Table 1). Staphylomatous changes were found in six patients, four of which were bilateral. Common peripheral fundus findings included spicule pigmentation (28 patients) and vascular attenuation (10 patients). Pale optic nerve head was reported in some patients (8 patients).

At least one full-field ERG was performed for 43 of the total 49 patients. Abnormalities noted on ERG were categorized into rod and/or cone system dysfunction and summarized in Table 2. Thirty-three out of 43 patients with an ERG had rod system dysfunction, and 42 out of 43 patients had cone system dysfunction. Twenty-six patients were reported to have CORD, three patients with cone dystrophy, and fifteen patients with rod-cone dystrophy (RCD, including nine patients with a retinitis pigmentosa (RP) clinical phenotype). Notably, only one patient (at age 8) presented with rod dysfunction without concomitant cone dysfunction.

Table 2.

Electroretinogram (ERG) findings for patients with CFAP410-associated retinal dystrophy

Patient ID Rod Dysfunction Cone Dysfunction ERG pattern
1 + + Cone-Rod
2 + + Rod-Cone
3 + + Cone-Rod
4 + + Cone-Rod
5 - + Cone
6 + + Rod-Cone
7 + + Cone-Rod
8 + + Cone-Rod
9 + + Cone-Rod
10 - + Cone
11 Not available Not available Not reported
12 - + Cone
13 + + Rod-Cone
14 + + Rod-Cone
15 + + Cone-Rod
16 + + Rod-Cone
17 + + Cone-Rod
18 - + Cone-Rod
19 Not available Not available Rod-Cone
20 - + Cone-Rod
21 + + Cone-Rod
22 Not available Not available Rod-Cone
23 Not available Not available Cone-Rod
24 - + Cone-Rod
25 + + Cone-Rod
26 - + Cone
27 + + Rod-Cone
28 + + Cone-Rod
29 + + Rod-Cone
30 - + Cone-Rod
31 + + Cone-Rod
32 + - Rod-Cone
33 + + Rod-Cone
34 Not available Not available Rod-Cone
35 + + Rod-Cone
36 + + Cone-Rod
37 + + Cone-Rod
38 - + Cone
39 - + Cone
40 + + Cone-Rod
41 + + Cone-Rod
42 + + Cone-Rod
43 + + Rod-Cone
44 Not available Not available Not reported
45 + + Cone-Rod
46 + + Cone-Rod
47 + + Cone-Rod
48 + + Cone-Rod
49 + + Rod-Cone
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Figure 2 summarizes imaging and ophthalmic findings of representative patients with CORD ordered from the least to the most advanced retinal disease. FAF findings ranged from peri-macular hyper-autofluorescence in more mildly affected patients to a bright, perifoveal hyper-autofluorescent ring with diffuse speckled hyper-autofluorescence and hypo-autofluorescence in the fundus periphery in more advanced cases. OCT showed diffuse fragmentation of the ellipsoid zone (EZ) in less advanced cases, and macular atrophy with loss of outer retinal layers in patients with more advanced disease.

Fig. 2. Fourteen representative patients with CFAP410-associated retinal dystrophy in order from least (top of the table) to most advanced (bottom of the table) cone-rod or cone dystrophy.

Fig. 2

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Rankings were made based on ophthalmic exam, visual symptoms, electroretinogram findings, fundus photography, fundus autofluorescence, and OCT (optical coherence tomography) imaging. Results of genetic testing, age of symptom onset, and age at most recent exam are also included.

Figure 3 summarizes imaging and ophthalmic findings of representative patients with RCD ordered from least to most advanced retinal disease. FAF findings ranged from a hyper-autofluorescent ring surrounding the macula in patients with less advanced disease to peripapillary hypo-autofluorescence and peripheral RPE atrophy in more advanced disease. On OCT, relative preservation of the retina was seen in less advanced disease, compared to more advanced disease with diffuse EZ fragmentation. One patient had a stage 4 lamellar hole with macular edema.

Fig. 3. Five representative patients with CFAP410-associated retinal dystrophy in order from least (top of the table) to most advanced (bottom of the table) rod-cone or rod dystrophy.

Fig. 3

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Rankings were made based on ophthalmic exam, visual symptoms, electroretinogram findings, fundus photography, fundus autofluorescence, and OCT (optical coherence tomography) imaging. Results of genetic testing, age of symptom onset, and age at most recent exam are also included.

Systemic findings

Systemic signs and symptoms screened for included reproductive abnormalities, kidney and urinary tract diseases, immunologic disorders, cancers, obesity, liver disease, neurologic diseases, and cognitive deficits (Supplementary Table 1). Three patients were reported to have reduced cognitive abilities, two of whom (Patients 47 and 48) reported neurologic symptoms including sensorineural hearing loss and mild peripheral neuropathy. Four patients underwent cerebral imaging, with findings ranging from normal (patient 34) to age-related parenchymal loss of cerebral cortex (patient 47) or Arnold Chiari malformation type 1 with cerebellar tonsillar herniation requiring surgical decompression (patient 38) (Supplementary Table 1). Reproductive abnormalities included one patient with late-onset puberty and two with erectile dysfunction. Diseases of the kidneys and urinary tract were uncommon, with one patient experiencing kidney stones, one patient with chronic kidney disease, and another patient with a history of proteinuria. No renal ultrasounds were on record in our cohort. No immunologic disorders or cancers were reported. No concomitant ciliopathies, including ALS or JATD, were present.

Skeletal abnormalities more complex than short stature were reported in 11 of the 49 patients, including abnormalities of the hip and femur (6 patients), chest and ribs (4 patients), and spine (7 patients). These findings are summarized in Supplementary Table 2. The most common skeletal findings were scoliosis (5 patients) and hip dysplasia (4 patients). Two patients were found to have short ribs with flared anterior ends (Supplementary Fig. 2). Patient 7 was born with pectus excavatum and narrow thorax corrected with early chest expansion surgery.

Eight patients had short stature, four of which were post-natal onset. Only patient 49 received a bone age scan, which found normal skeletal maturation, and was treated with growth hormone to which no response was recorded. Six patients with the p.Arg73Pro variant were not found to have skeletal abnormalities, including patient 18 (age 18 at most recent exam), patient 27 (age 69), patient 28 (age 67), patient 30 (age 7), patient 31 (age 22), patient 45 (age 65). Five patients had no skeletal examination reported in their medical records, their ages range from 9 to 43 at most recent exam.

Discussion

We present a large cohort of subjects with CFAP410-associated retinal degeneration. While the retinal phenotype of patients in this cohort is highly variable, we found that most patients present with an onset of visual symptoms early in life (mean age of 11.4 years), with progression to severe retinal dystrophy later in life. CFAP410-associated retinal degeneration most commonly displays a CORD pattern, and only about one third of patients had a RCD/RP phenotype. This ratio is consistent with previously observed cohorts which found a CORD pattern in association with CFAP410 variants approximately twice as frequently among 36 confirmed cases9,10,12–18.

The most common visual symptom in our cohort was decreased visual acuity, which was reported by all patients. A recent review of 36 cases of CFAP410 related retinopathies determined that only 61% experienced decreased visual acuity18. This difference could be the result of our cohort being selected from the records of ophthalmological centers specialized for inherited retinal disease, whereas published CFAP410 cases may have only been evaluated for retinal findings after a skeletal phenotype was observed. Other common visual symptoms within this cohort included photophobia, delayed light-to-dark adaptation times, reduced color vision in patients with a CORD phenotype, and nyctalopia in patients with the RCD/RP phenotype, which is consistent with previous reports21–29.

CFAP410 has two highly conserved domains, the LRR and the LRRCT, which have been implicated in CFAP410 protein stability and are essential for the interaction between CFAP410 and NEK18,9. Patients in this cohort with pathogenic variants expected to abolish the stability of these conserved regions tended to have earlier onset of visual symptoms, and they were more likely to have skeletal abnormalities as compared to patients with variants outside of these conserved regions (Supplementary Fig. 3). The p.Arg73Pro variant has a proline residue substituted into the LRR region, which is predicted to sterically clash with four residues in the LRR and one residue in the LRRCT (Supplementary Fig. 4), potentially precluding binding with NEK15. While modeling the structural consequences of sequence variants in conserved regions cannot fully account for the observed phenotypes among our patients, a majority of the patients with documented skeletal abnormalities in our cohort had at least one copy of p.Arg73Pro, consistent with previous reports3,7,18.

In contrast to the deleterious p.Arg73Pro variant, patients with p.Glu96Lys, a variant that falls outside of the conserved LRR and LRRCT regions (Supplementary Fig. 5), were found to have an onset of retinopathy in the fourth decade of life and were not found to have skeletal abnormalities. While this substitution is predicted to abolish a hydrogen bond between the wildtype glutamate residue at position 96 in the amino acid sequence and an arginine residue at position 70 within the LRR, it is not predicted to yield conformational changes within conserved regions of CFAP410, likely preserving interaction with NEK1. Three patients were homozygous for the p.Glu96Lys variant and demonstrated relatively milder ophthalmologic findings and later onset of symptoms compared to the rest of the cohort. To our knowledge, homozygous p.Glu96Lys variants have not been previously reported clinically. Variants in these highly conserved regions alone cannot fully account for inconsistencies between these genotypes and observed phenotypes.

Eleven of the 46 patients had skeletal abnormalities, and those with skeletal abnormalities tended to have milder skeletal phenotypes than what has been reported in literature. Multiple recent cohorts have identified patients homozygous for p. Arg73Pro, all with severe skeletal abnormalities, including platyspondyly, hip dysplasia, and thoracic dysplasia consistent with SMDAX3,7. No patients in the current study were found to have lacy iliac crests, and only two were found to have anterior rib cupping, both recognized as distinguishing features of SMDAX21. Notably, there are scant reports of patients homozygous for p. Arg73Pro without skeletal abnormalities. Six are reported in the present study (ages ranged from 7 to 69). This finding may be influenced by collecting patient records without a standardized skeletal exam from ophthalmic centers. While five patients in the current study did not have any skeletal exams reported in their medical records, it can be assumed that any potential skeletal abnormalities among these seven patients are relatively mild and have not required medical or surgical intervention. This discrepancy in phenotypic severity may indicate that the retinal phenotype is under-reported relative to the skeletal phenotype, and that there is a wide range of variability in CFAP410-related skeletal abnormalities.

Clinical findings associated with ciliopathies beyond ophthalmic and skeletal abnormalities were rare, including renal abnormalities (only patient 33), reduced cognitive abilities (patient 31), obesity (5 patients, none of whom demonstrated short stature), and reproductive abnormalities (patient 13). Liver disease, known to be associated with Jeune’s asphyxiating thoracic dystrophy (JATD), was not present. Recognition has been increasing of CFAP410 as an ALS-associated protein30, and two patients are noted to have ALS and variants in CFAP410-associated retinal dystrophy in a recently published review19. ALS was not present among our patients. Cerebral imaging was relatively infrequent among this study, as were reports of neurological disorders.

Among reported cases of CFAP410-associated retinal dystrophy, 36 comparable cases were found. In combination with our 49 cases, total counts of ophthalmic and systemic findings are as follows: CORD (37 cases), RD/RP (20 cases), short stature15, Rhizomelic shortness4, ALS2, JATD5, SMDAX10, delayed puberty2, Crohn’s1, pectus carinatum1, pectus excavatum1, Narrow thorax11, brachydactyly1, scoliosis12, delayed bone age2, short ribs3, platyspondyly4, dysplastic hips5, and hearing deficits5,14–19.

Multiple sequence variants in this cohort appeared to be severely deleterious, as the affected patients tended to present in the first decade of life with advanced retinal dystrophy as assessed by ERG and fundus autofluorescence (FAF). One such variant was p. Ala12SerfsTer60, which was heterozygous in four patients (compound heterozygotes) in this cohort. The pattern of retinal degeneration of these patients included CORD (one patient), RCD (one patient), cone dystrophy (one patient), and one patient without ERG on record. This variant was previously reported in two patients, one with RP and the other with CORD, although no additional clinical data was reported19. Two of these four patients had skeletal abnormalities beyond short stature, one of which was consistent with SMDAX. This indel sequence variant truncates the CFAP410 protein near the middle of the LRR (Supplementary Fig. 6), likely abolishing interaction with NEK1.

Two deleterious variants disrupted the LRRCT, which functions as a cap for the LRR superhelix9. Two patients homozygous for the novel p.Met109AlafsTer10 variant were found to have RP, reduced BCVA by their second decade of life, and neither had skeletal abnormalities. The rare inframe duplication, p.Thr114_Arg117dup, is heterozygous in two patients in our cohort. One had a pattern of CORD, and the other a pattern of RCD, and this variant is previously reported in one patient with CORD, staphyloma, and short stature9. Notably, one of our patients with this variant had advanced skeletal abnormalities consistent with SMDAX, whereas the previously reported patient did not9. Computer models from Chiu et al.10 predict the p.Thr114_Arg117dup variant to have an exposed inner core of hydrophobic residues within the LRR superhelix (Supplementary Fig. 7). More research is needed to determine the consequences of these variants.

There was a diverse range of pathogenic alleles within this cohort. Aside from the common p.Arg73Pro variant, present in at least one allele in 20 patients, no other pathogenic variant was present in more than four subjects (Table 1). This is comparable to previous cohorts of CFAP410 patients, including a recent review of 36 published patients where almost a third of the cohort had at least one copy of p.Arg73Pro17. The p.Arg73Pro allele was the most frequent variant among our patients, and all patients with ethnicity reported in their medical records had European ancestry within their immediate family (17 out of 21). This is consistent with genomic databases which report p.Arg73Pro to be the most frequent variant and most commonly find European ancestry among reported cases and a rather high MAF in the general population (Supplementary Table 3)31,32. Most variants in the current study were only present in one or two alleles of the total of 98 alleles, which limits this study’s ability to draw conclusions about genotype-phenotype relationships.

This retrospective study has several limitations. The methods of data collection may vary among centers, and fundus imaging was not collected using a standard protocol. Description of exam findings were not standardized. Genetic testing varied among the different testing laboratories utilizing different size gene panels and various strategies (e.g., NGS, WES, WGS). Follow-up intervals were not standardized. Data regarding skeletal manifestations of disease may be limited as some patients were primarily evaluated by eye care providers and did not undergo a full systemic evaluation.

In conclusion, we have reported 49 patients with a range of CFAP410-associated retinal dystrophies and skeletal abnormalities. Our findings demonstrate that most affected patients develop a CORD pattern with an early onset of visual symptoms during childhood. Much remains to be discovered regarding the genotype-phenotype relationships of this rare ciliopathy, and we suggest that longitudinal follow-up of these patients will elucidate the progression of CFAP410-associated retinal dystrophy. A detailed ophthalmological examination should also be recommended for all SMDAX patients, as it would allow us to better estimate the true frequency of ophthalmic manifestations in this condition and the spectrum thereof.

Methods

An observational, retrospective, multi-center study of 49 patients was conducted. Inherited retinal disease specialists from 20 ophthalmic genetics centers around the world identified relevant cases with confirmed, likely biallelic CFAP410 sequence variants for this case series. Patients were excluded from the study if they had pathogenic variants in other known retinal dystrophy-associated genes that would be sufficient to cause retinal disease.

Demographic information including sex, age, and known family history was obtained. Molecular data, clinical data, imaging, and electrophysiological findings (when available) were reported. Clinical data collected included best-corrected visual acuity (BCVA), age at first visual symptoms, slit-lamp biomicroscopy, ophthalmoscopy findings and systemic findings. This work was approved through the Oregon Health & Science University Institution Review Board (IRB #2735). Informed consent for all human participants was obtained. We have complied with all relevant ethical regulations including the Declaration of Helsinki.

Image and functional analysis

Images of 98 eyes from 49 patients were reviewed and interpreted by retina specialists from each center. Types of imaging included fundus photography, FAF, and optical coherence tomography (OCT). When available, electroretinogram (ERG) findings were also reported.

Molecular analysis

Genetic testing was performed in one of several CLIA-certified laboratories including Blueprint Genetics, Variantyx, Molecular Vision Laboratory, and Invitae for US patients and analyses, other accredited genetic diagnostic laboratories (Europe), or within a research setting using various techniques including panel, exome, and genome-sequencing. The likely disease-causing CFAP410 variants are reported as stated in the patients’ genetic reports (Table 1).

Variant nomenclature of the CFAP410 variants adhered to HGVS variant description recommendations (http://varnomen.hgvs.org/) and was based on NCBI reference sequence (NM_004928.3) and Ensembl gene and transcript reference sequences ENSG00000160226.16/ ENST00000339818.9 comprising 7 coding exons.

Variant classification within this research study was performed according to American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al.31) guidelines using the web-based variant interpretation tool Franklin applying custom settings (Genoox Ltd, https://franklin.genoox.com/).

Minor allele frequencies were retrieved from the Genome Aggregation Database (gnomAD) (v2.1.1) (https://gnomad.broadinstitute.org/).

Protein modeling

The predicted structures of wild-type and mutant proteins were modeled using ChimeraX-1.6.120 Amino acid sequences were obtained from the UniProt database (https://www.uniprot.org/uniprotkb/O43822/entry).

Supplementary information

Supplementary Information (1.3MB, pdf)

Acknowledgements

The authors thank the patients and their family members for participation in this study. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This work was supported by the National Institutes of Health (Bethesda, MD) P30 EY010572 core grant, the Malcolm M. Marquis, MD Endowed Fund for Innovation and an unrestricted grant from Research to Prevent Blindness (New York, NY) to Casey Eye Institute, Oregon Health & Science University. This research was also supported, in part, by the UCSF Vision Core shared resource of the NIH/NEI P30 EY002162, the Foundation Fighting Blindness, and the Research to Prevent Blindness Unrestricted grant.

Author contributions

R.E.S. led data collection, data analysis, and manuscript writing. The following authors contributed to data collection, data analysis, and manuscript writing and revision: A.E.P., D.B., K.J., J.D., R.A., B.L., E.J., N.J., M.G., O.M., A.W., M.M., B.B., A.I., A.V., D.C.P., E.H., H.S., L.J-K., E.T., W.Z., B.B, C.C., R.H., T.A., M.S., S.T., M.A., J.S., M.B.G., M.M.V.G., K.S., M.R., S.K., RA., J.S., A.L.V., S.H., J.D., J.H., M.T., J.M., U.G., S.K., W.B., C.G-K., M.M., L.E., P.Y., and M.E.P. provided clinical and genetic patient data as well as manuscript revision.

Data availability

Deidentified participant data will be shared upon request. We will provide the dataset that would be necessary to interpret, replicate, and build upon the methods and findings reported in the article. Data can be access by through contacting the author’s email address: schmidry@ohsu.edu.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41525-025-00489-1.

References

  • 1.Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med.364, 1533–1543 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Abu-Safieh, L. et al. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res.23, 236–247 (2013). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Wheway, G. et al. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell Biol.17, 1074–1087 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Scott, H. S. et al. Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis. Genomics47, 64–70 (1998). [DOI] [PubMed] [Google Scholar]
  • 5.Gregorczyk, M. et al. Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases. Life Sci. Alliance6, e202201740 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Wang, Z. et al. Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. J. Hum. Genet.62, 503–506 (2017). [DOI] [PubMed] [Google Scholar]
  • 7.Wang, Z., et al. Axial spondylometaphyseal dysplasia is caused by C21orf2 mutations. PLoS ONE11, e0150555 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Fang, X. et al. The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta Biochim. Biophys. Sin.47, 834–841 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Thiel, C. et al. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am. J. Hum. Genet.88, 106–114 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Chiu, N. et al. A homozygous in-frame duplication within the LRRCT consensus sequence of CFAP410 causes cone-rod dystrophy, macular staphyloma and short stature. Ophthalmic Genet.43, 378–384 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Dao, T. P., Majumdar, A. & Barrick, D. Capping motifs stabilize the leucine-rich repeat protein PP32 and rigidify adjacent repeats. Protein Sci.23, 801–811 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Dao, T. P., Majumdar, A. & Barrick, D. Highly polarized C-terminal transition state of the leucine-rich repeat domain of PP32 is governed by local stability. Proc. Natl. Acad. Sci. USA112, E2298–E2306 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Suga, A. et al. Identification of novel mutations in the LRR-cap domain of C21orf2 in Japanese patients with retinitis pigmentosa and cone-rod dystrophy. Investig. Ophthalmol. Vis. Sci.57, 4255–4263 (2016). [DOI] [PubMed] [Google Scholar]
  • 14.Khan, A. O., Eisenberger, T., Nagel-Wolfrum, K., Wolfrum, U. & Bolz, H. J. C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium. Br. J. Ophthalmol.99, 1725–1731 (2015). [DOI] [PubMed] [Google Scholar]
  • 15.McInerney-Leo, A. M. et al. Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: extending the phenotypic spectrum. Am. J. Med. Genet. A173, 1698–1704 (2017). [DOI] [PubMed] [Google Scholar]
  • 16.Isidor, B. et al. Axial spondylometaphyseal dysplasia: confirmation and further delineation of a new SMD with retinal dystrophy. Am. J. Med. Genet. A152A, 1550–1554 (2010). [DOI] [PubMed] [Google Scholar]
  • 17.Suzuki, S. et al. Axial spondylometaphyseal dysplasia: additional reports. Am. J. Med. Genet. A155A, 2521–2528 (2011). [DOI] [PubMed] [Google Scholar]
  • 18.Shinbashi, M., Jewell, A., Randolph, J. & Couser, N. C21orf2 variants causing inherited retinal disease: a review of what we know and a report of two new suspected cases. Clin. Case Rep.11, e7110 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Watanabe, Y. et al. An amyotrophic lateral sclerosis-associated mutant of C21ORF2 is stabilized by NEK1-mediated hyperphosphorylation and the inability to bind FBXO3. iScience23, 101491 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci.30, 70–82 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Carss, K. J. et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am. J. Hum. Genet.100, 75–90 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Shin, D. H. et al. Identification of the CFAP410 pathogenic variants in a Korean patient with autosomal recessive retinitis pigmentosa and skeletal anomalies. Korean J. Ophthalmol.34, 500–502 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Wang, L. et al. Application of whole exome and targeted panel sequencing in the clinical molecular diagnosis of 319 chinese families with inherited retinal dystrophy and comparison study. Genes.9, 360 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.de Castro-Miró, M. et al. Novel candidate genes and a wide spectrum of structural and point mutations responsible for inherited retinal dystrophies revealed by exome sequencing. PLoS ONE11, e0168966 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Buratti, E. et al. Aberrant 5’ splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res.35, 4250–4263 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hayman, T. et al. Whole exome sequencing of 491 individuals with inherited retinal diseases reveals a large spectrum of variants and identification of novel candidate genes. J. Med. Genet.61, 224–231 (2024). [DOI] [PubMed] [Google Scholar]
  • 27.Weisschuh, N. et al. Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases. J. Med. Genet.61, 186–195 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Huang, L. et al. Molecular genetics of cone-rod dystrophy in Chinese patients: new data from 61 probands and mutation overview of 163 probands. Exp. Eye Res.146, 252–258 (2016). [DOI] [PubMed] [Google Scholar]
  • 29.Rodríguez-Muñoz, A. et al. Expanding the clinical and molecular heterogeneity of nonsyndromic inherited retinal dystrophies. J. Mol. Diagn.22, 532–543 (2020). [DOI] [PubMed] [Google Scholar]
  • 30.Zelina, P. et al. ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons. Acta Neuropathol. Commun.12, 144 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med.17, 405–424 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Chen, S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature625, 92–100 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Information (1.3MB, pdf)

Data Availability Statement

Deidentified participant data will be shared upon request. We will provide the dataset that would be necessary to interpret, replicate, and build upon the methods and findings reported in the article. Data can be access by through contacting the author’s email address: schmidry@ohsu.edu.

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