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. Author manuscript; available in PMC: 2025 Oct 1.
Published in final edited form as: Ophthalmic Genet. 2024 Sep 10;45(5):546–550. doi: 10.1080/13816810.2024.2401850

A novel large multi-gene deletion in syndromic choroideremia

Emily H Jung 1, Anna Duemler 1, Alessandro Iannaccone 1,2,3, Oleg Alekseev 1
PMCID: PMC11443535  NIHMSID: NIHMS2023584  PMID: 39257251

Abstract

Introduction

Caused by mutation or deletion of the CHM gene, choroideremia is a rare X-linked recessive chorioretinal dystrophy characterized by progressive degeneration of the retinal pigment epithelium, photoreceptors, and the choriocapillaris. There are few published reports of choroideremia associated with complex syndromic phenotypes due to large or contiguous gene deletions.

Methods

Case report and review of literature.

Results

We present a case of a 46-year-old male with a prior clinical diagnosis of syndromic retinitis pigmentosa, who was found to have syndromic choroideremia associated with a novel multi-gene deletion of 13.5 megabase pairs. This deletion encompassing 18 genes is one of the largest deletions reported in the literature. A total of 18 male cases of choroideremia associated with confirmed large or contiguous gene deletions have been published to date. Previously reported deletions range in size from 4 to 15 megabase pairs, and observed phenotypes include cleft lip and palate, ptosis, obesity, metabolic diseases, developmental delay, and hearing loss.

Discussion

The contribution of our case aims to expand our understanding of Xq21 deletions and prompts further investigation of genes found in this locus. Furthermore, it highlights the importance of including syndromic choroideremia on the differential diagnosis in the workup of other syndromic retinopathies, particularly those that feature obesity, hearing loss, or intellectual disability.

Keywords: Choroideremia, CHM, chorioretinal, IRD

Introduction

Choroideremia is a rare X-linked recessive chorioretinal dystrophy characterized by progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors, and the choriocapillaris. This dystrophy, with an estimated prevalence of 1 in 50,000 to 100,000, is caused by mutation or deletion of the CHM gene, which encodes Rab escort protein (REP1), a protein involved in geranylgeranylation and intracellular vesicle transport. There are few published reports of choroideremia associated with complex syndromic phenotypes due to large or contiguous gene deletions (Table 1).1,2 We present a case of syndromic choroideremia associated with a novel large multi-gene deletion of 13.5 megabase pairs (Mbp).

Table 1.

Summary of published cases of syndromic choroideremia.

Patient Deleted region Systemic features
Reference Age (yrs) Size (Mbp) Locus Involved genes DD HL Ob Other
Van den Bosch 1959 3 7 - - - + - - Acrokeratosis verruciformis, anhidrosis, skeletal deformity
Van den Bosch 1959 9 - - - + - - Acrokeratosis verruciformis, anhidrosis, skeletal deformity
Ayazi 1981, Nussbaum 1987, Merry 19894,13,14 30 5.3 - - + + +
Ayazi 1981, Nussbaum 1987, Merry 1989 19 12 - - - + + Bronchial asthma
Ayazi 1981 54 - - - + + +
Tabor 1983, Rosenberg 1986, Schwartz 198815–17 2 15 Xq21.1q21.33 - + - - Agenesis of corpus callosum, cleft lip and palate, coarse facial features, hypertelorism, macrocephaly, cubitus valgus, decreased truncal muscle tone
Hodgson 1987, Cremers 198918,19 8 15 Xq21.21q21.33 - + - - High arched palate, maxillary prognathism
Nussbaum 1987 - - Xq21 - + + - Short stature
Nussbaum 1987 - - Xq21 - + + - Short stature
Rosenberg 1987, Schwartz 198820 7 - Xq21.2q21.31 - + + -
Rosenberg 1987 19 - Xq21.2q21.31 - + + - Epilepsy
Poloschek 2008 21 15 8.5–14.1 - FAM121A, POF1B, CHM, DACH2, KLHL4, CPXCR1, NAP1L3 + + -
Poloschek 2008 21 6.3–9.7 - FAM121A, POF1B, CHM, DACH2, KLHL4, CPXCR1, USP12P2, PABPC5 + - - Reduced facial expression, unilateral postural destabilization, delayed finger tapping, dysdiadochokinesis
Poloschek 2008 18 6.3–9.7 - FAM121A, POF1B, CHM, DACH2, KLHL4, CPXCR1, USP12P2, PABPC5 - - - Fine motor disability
Rush 2010 11 16 - Xq21.1q21.33 POU3F4, ZNFG, CHM, PABPC5, MGC1, BTK, PAK3/MRX30 + + - Cerebellar vermis hypoplasia, cleft lip, alveolar notching, mild retrognathia, hyperactive behavior, poor attention span, aggressiveness, Mondini malformation
Lee 2015 12 58 4.5 Xq21.1q21.31 UBE2DNL, APOOL, SATL1, ZNF711, POF1B, CHM, DACH2, KLHL4, CPXCR1 - - - Diabetes
Lee 2015 32 4.5 Xq21.1q21.31 UBE2DNL, APOOL, SATL1, ZNF711, POF1B, CHM, DACH2, KLHL4, CPXCR1 - - -
Liang 2017 10 17 8.05 Xq21.1q21.31 POU3F4, CYLC1, RPS6KA6, HDX, APOOL, SATL1, ZNF711, POF1B, CHM, DACH2, KLHL4, CPXCR1 + + - Narrow forehead, ptosis, short palpebral fissures, prominent ears
Present case 46 13.5 Xq21.1q21.33 APOOL, CHM, CPXCR1, CYLC1, DACH2, DIAPH2, FAM133A, HDX, KLHL4, NAP1L3, PABPC5, PCDH11X, POF1B, RPA4, RPS6KA6, SATL1, TGIF2LX, ZNF711 + - + Diabetes, ptosis, non-alcoholic fatty liver disease, non-rheumatic mitral regurgitation
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DD – developmental delay

HL – hearing loss

Mbp – megabase pairs

Ob – obesity

Report of case.

A 46-year-old male with a prior clinical diagnosis of syndromic retinitis pigmentosa and no significant family history was referred for further evaluation. He had experienced nyctalopia and visual field limitation since early childhood, and recently noted worsening photopsia. His best-corrected visual acuity was 20/80 in the right eye and 20/126 in the left eye. Slit lamp examination was notable for bilateral ptosis and dermatochalasis. Dilated fundus examination revealed bilateral diffuse RPE atrophy, retinal thinning, vascular attenuation, and scattered nummular pigment deposits peripherally (Figure 1A,B). Spectral domain optical coherence tomography (OCT) of the macula demonstrated generalized loss of the ellipsoid zone, severe attenuation of the outer nuclear layer, hypertransmission defects, mild intraretinal cysts (IRCs), and mild focal choroidal excavations in inferonasal macula (Figure 1E–H). Fundus autofluorescence imaging showed generalized hypoautofluorescence with a small scalloped central area of hyperautofluorescence (Figure 1C,D). Full-field electroretinogram responses were essentially non-recordable in both eyes. Medical history was notable for truncal obesity [body mass index (BMI) of 36], developmental delay, non-rheumatic mitral regurgitation, non-alcoholic fatty liver disease, and type 2 diabetes mellitus. Audiologic examination demonstrated no hearing deficits. Genetic testing with next-generation sequencing and subsequent cytogenic microarray analysis revealed a large multi-gene deletion within cytogenetic band Xq21.1q21.33 (13.5 Mbp), including the following genes: APOOL, CHM, CPXCR1, CYLC1, DACH2, DIAPH2, FAM133A, HDX, KLHL4, NAP1L3, PABPC5, PCDH11X, POF1B, RPA4, RPS6KA6, SATL1, TGIF2LX, and ZNF711, as well as four microRNAs (MIR361, MIR1321, MIR548I4, and MIR548M) (Figure 2).

Figure 1.

Figure 1.

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Multimodal retinal imaging, including widefield pseudocolor fundus photographs (A,B), fundus autofluorescence imaging (C,D), and macular OCT scans through the foveola (E,F) and through inferior macula (G,H), of the right and left eye, respectively. Arrows indicate focal choroidal excavations.

Figure 2.

Figure 2.

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Microarray analysis showing a multi-gene deletion on the X-chromosome (bottom panel) within cytogenetic band Xq21.1q21.33 (top panel). Genomic coordinates within Genome Reference Consortium Human Build 37 (GRCh37): 82,970,574–96,468,515.

Discussion.

Choroideremia was first reported in association with other systemic features in 1959. Termed “van den Bosch syndrome,” the exhibited phenotypes included developmental delay, acrokeratosis verruciformis, anhidrosis, and skeletal deformity.3 Syndromic choroideremia was subsequently described in 1981 in three generations of a family with choroideremia, obesity, and congenital deafness.4 A total of 18 male cases of choroideremia associated with confirmed large or contiguous gene deletions have been published in the literature to date (Table 1). Median age at presentation is 17.5 years (range, 2–58), and all patients are male. Previously reported deletions range in size from 4 to 15 Mbp. Observed phenotypes include cleft lip and palate, ptosis, obesity, metabolic diseases, developmental delay, and hearing loss, of which developmental delay (78%, 14/18) and hearing loss (56%, 10/18) have been the most commonly observed. Systemic features of this rare condition can mimic other syndromic retinopathies, particularly Oliver-McFarlane syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome, and Alström syndrome, further complicating the diagnosis.5 However, common features of these other syndromes, such as trichomegaly, pituitary hormone deficiencies, hypogonadism, polydactyly, renal dysfunction, hearing loss, and dilated cardiomyopathy, were not present in our patient.

Of the 18 genes deleted in our patient, three are firmly established to cause human pathology: CHM (choroideremia), ZNF11 (intellectual disability), and POF1B (premature ovarian failure).6–8 Similar deletions have also been reported to involve POU3F4, which facilitates inner ear development.9 Hearing loss was reported in 10 of 18 patients, and of the two cases that specifically identified POU3F4 deletions, both had hearing loss.10,11

Our case describes one of the largest known gene deletions in syndromic choroideremia, which partially overlaps with the deletions reported in prior cases of syndromic choroideremia. Of note, compared to previously published cases, our patient presented with rather mild systemic features despite a large deletion region. Although, it remains unclear whether the mitral valve regurgitation and non-alcoholic fatty liver disease seen in our patient can be attributed to this multi-gene deletion. Similarly, in a family with choroideremia, two individuals with deletions of 4.5 Mbp did not present with any syndromic features.12 Unfortunately, the broad variability of syndromic penetrance complicates genotype-phenotype correlations and hampers the identification of genes responsible for various systemic features observed in these patients.

The contribution of our case expands our understanding of Xq21 deletions and prompts further investigation of genes found in this locus. It also highlights the importance of including syndromic choroideremia on the differential diagnosis in the workup of other syndromic retinopathies, particularly those that feature obesity, hearing loss, or intellectual disability.

Funding

This work was supported by the National Eye Institute grant EY033857 (OA) and Duke University Physician-Scientist Strong Start Award (OA).

Footnotes

Author contributions statement

Conception and design: AI, OA

Data analysis and interpretation: EHJ, AD, AI, OA

Drafting of the manuscript: EHJ, OA

Critical revision of the manuscript: EHJ, AD, AI, OA

Final approval of the version to be published: EHJ, AD, AI, OA

All authors agree to be accountable for all aspects of the work.

Statements and declarations: The authors report no conflicts of interest.

Disclosure statement

No potential conflict of interest was reported by the authors.

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