A systematic review of inherited retinal dystrophies in Pakistan: Updates from 1999 to April 2023

doi:10.21203/rs.3.rs-3007939/v1

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Research Article

A systematic review of inherited retinal dystrophies in Pakistan: Updates from 1999 to April 2023

https://doi.org/10.21203/rs.3.rs-3007939/v1

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Journal Publication

published 05 Feb, 2024

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Background

Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023.

Methods

Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines.

Results

A total of 359 sequence variants in 89 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 90% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (43%), followed by frameshift (26%), nonsense (18.7%), splice site (12%) and synonymous change (< 1%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77% vs. 23%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber’s congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene.

Conclusion

In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of pathogenic variants in homozygous state.

Inherited retinal degenerations

consanguinity

homozygous

monogenic disorders

Pakistan

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically diverse eye disorders ranging in prevalence from 1 in 2000 to 1 in 4000 people globally [1, 2]. Major clinical manifestations of IRDs include, but not limited to, night blindness or nyctalopia, color vision deficiency, photophobia, nystagmus, reduced visual acuity, day vision loss as well as central or peripheral vision loss, deafness, obesity, intellectual disability. These symptoms may appear isolated (non-syndromic) or in combination with extra-ocular phenotypes (syndromic) and can leads to legal blindness or permanent vision loss [3–6]. Globally, mutations in over 300 distinct genes have thus far been associated with all forms of IRDs [3]. IRDs follow all modes of Mendelian inheritance such as autosomal recessive[7], autosomal dominant[8], X-linked[9], mitochondrial [10] as well as digenic [11] and oligogenic patterns [12]. IRDs are classified into various subtypes depending upon disease onset, mode of inheritance, rate of disease progression, clinical presentation, part of retina affected (rods, cones, retinal pigment epithelium, inner retina and choroid), and involvement of extra ocular phenotypes [13]. These sub-types are briefly explained in the following sections.

Cone or Cone-Rod dystrophy (CD/CRD)

Cone and cone-rod dystrophies (CD/CRD) are a rare form of retinal dystrophies with a worldwide prevalence rate of 1:40,000 [14]. CD/CRD are progressive disorders of cone and rod photoreceptor cells in retina presenting clinical and genetic heterogeneity [4]. Major clinical symptoms of CD include reduced day vision, color vision deficiency, reduced visual acuity, and photophobia [15]. Similarly, CRD is initially characterized by rods dysfunction resulting in night blindness (nyctalopia) followed by deterioration of cones that eventually leads to progressive loss of day vision as well. However, symptoms such as photophobia, color vision deficiency, and legal blindness overlap between CD and CRD. In either case, electroretinogram (ERG) appears to show non-recordable pattern [16]. CD/CRD may transmit as autosomal recessive, autosomal dominant or X-linked entity with mutations in as many as 32 distinct genes identified thus far [17]. Gill and colleagues have reported that 62.2% cases of recessively inherited CD/CRD are linked to mutations in ABCA4 gene. Similarly, of the dominantly inherited CD/CRD, 34.6% cases are caused by mutations in GUCY2D gene. Lastly, of the X-linked inherited CD/CRD, 73.0% cases are due to mutations in RPGR gene [18].

Congenital Stationary Night Blindness (CSNB)

Congenital stationary night blindness (CSNB) is a form of non-progressive inherited retinal dystrophy that mostly appears in early childhood [19]. Visual symptoms include night blindness, nystagmus and reduced visual acuity [20]. ERG findings show normal cone response; however, reduced or abolished rod response is detected on ERG in CSNB. Similarly, fundoscopy mostly remains unremarkable [21]. CSNB follows all modes of inheritance (AR/AD/XL) [20]. As per RetNet [RetNet - Retinal Information Network (uth.edu)], at least 13 genes are thus far known to cause CSNB, including 10 genes for AR-CSNB, 1 gene for AD-CSNB, and 2 genes for XL-CSNB.

Leber Congenital Amaurosis (LCA)

Leber’s congenital amaurosis (LCA) is a rare, and one of the most clinically severe form of IRDs with a worldwide prevalence of 1:80,000 [22]. LCA is, typically, associated with early onset vision loss, nystagmus, and amaurotic pupils [23]. Clinical pattern includes pigmentory retinopathy, reduced or absent ERG response, poor central vision or complete blindness at birth [24]. LCA follows autosomal recessive inheritance pattern [25], and account for approximately 5% of the total IRDs [26], and ~ 20% of childhood blindness [23]. So far, pathogenic variants in 38 genes are known to cause LCA [23]. Some of the frequently mutated genes in LCA include AIPL1, CEP290, CRB1 and GUCY2D [27].

Macular degeneration (MD)

Macular degeneration (MD) is a heterogeneous group of progressive eye disorders characterized by bilateral symmetrical macular abnormalities and macular flecks. Visual complaints include, reduced visual acuity, central vision loss, photophobia, slow dark adaptation, and nystagmus [28]. Stargardt (STGD) disease is the most common form of macular dystrophy with a prevalence rate of 1 in 8000–10000 [29]. STGD1 follows an autosomal recessive mode of inheritance with ABCA4 as the leading cause of the disease that accounts for 95% STGD1 cases [30]. Of the total 18 genes associated with MD, 14 genes are responsible for AD-MD while the remaining 4 genes results in AR-MD [RetNet - Retinal Information Network (uth.edu), accessed on March 6, 2023].

Retinitis Pigmentosa (RP)

Retinitis pigmentosa (RP), with a worldwide incidence rate of 1:3000 to 1:4000, appears as the most highly frequent type of IRDs [31]. Though symptoms and onset of RP is largely variable, it usually starts with night blindness during first or second decade of life due to the degeneration of rod photoreceptor cells. This is followed by visual field constriction (tunnel vision) and degeneration of cone photoreceptors, finally leading to complete blindness by late third or early fourth decade of life. Auxiliary symptoms may include photophobia, nystagmus and reduced visual acuity [31]. Around 70%-80% of RP cases are non-syndromic (isolated) while the remaining 20–30% cases are associated with non-ocular manifestations, and thus classified as syndromic RP [32]. RP may be inherited as an autosomal dominant (15–25%), autosomal recessive (5–20%), X-linked (5–15%) [33, 34], or a di-genic entity [35] with associated mutations reported in over 132 different genes [RetNet - Retinal Information Network (uth.edu)]. Mutations in RPGR gene is the leading cause of X-linked RP [36].

Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare ciliopathy with multisystem involvement [37]. Hallmark features of BBS include obesity, macro or micro-cephaly, night blindness, cone-rod dystrophy, retinitis pigmentosa (RP), hypodontia, dental crowding, hepatic fibrosis, hypogonadism, hypogenitalism, tricuspid regurgitation, dilated cardiomyopathy, renal anomalies, polydactyly, brachydactyly, syndactyly, delayed development, mental retardation, ataxia, speech disability speech delay, and diabetes mellitus [38, 39]. However, these symptoms may vary from person to person. Since the mutated genes in BBS have functional relevance in ciliary biogenesis and trafficking, the condition is regarded as ciliopathy [40]. To our knowledge, mutations in at least 21 genes/loci are so far linked to BBS, all following an autosomal recessive inheritance pattern [41] and in some cases oligogenic [42]. Interestingly, ~ 50% of the BBS cases are associated with pathological sequence variations in three genes, namely, BBS1, BBS2, and BBS10 [43].

Usher Syndrome (USH)

Usher syndrome (USH) is a rare form syndromic IRDs, presenting deafness in conjunction with blindness, that affect people with a worldwide prevalence of between 4–17 in 100000 [44] [45]. Chief ocular complaints are night blindness, progressive vision loss, nystagmus whereas non-ocular symptoms include hearing difficulty or sensorineural hearing loss of variable degree [46]. USH is sub-divided into different types, for example, USH1, USH2 and USH3, based upon clinical presentation of the disease. USH2 is the predominant type among all sub-types [47]. USH is passed in an autosomal recessive pattern [48], and di-genic [49] with mutation in 10 genes thus far known to cause the disease. While mutations in USH2A gene account for roughly 80% of USH2 cases, MYO7A gene mutations are responsible for over 50% of USH1 cases [50].

Joubert syndrome

Joubert syndrome (JBTS) is an infrequent genetic ciliopathy characterized by the involvement of multiple systems and organs, including the brain, kidneys, liver, and eyes. The clinical presentation of JBTS typically involve mild to moderate mental retardation, macrocephaly, retinal dystrophy, nystagmus, coloboma, visual impairment, hepatic and renal anomalies, and skeletal deformities with characteristic “molar tooth sign” on MRI. Given its rarity as a genetic ciliopathy, JBTS has a global occurrence rate of 1 in 80,000 to 1 in 100,000 live births [51]. JBTS is predominantly inherited as an autosomal recessive disorder [52]. However, there have been reports of X-linked inheritance due to mutations in the OFD1 gene [51]. Pathogenic sequence variations in at least 40 genes have been associated with JBTS so far [53]. Mutations in AIH1 and CEP290 gens account for approximately 38% of genetically diagnosed JBTS patients [51].

Senior-Loken Syndrome

Senior-Loken syndrome (SLS) is a rare syndromic form of IRDs that is estimated to affect 1 in 1,000,000 individuals worldwide. The disease is characterized by retinopathy that may progress as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), or sector RP. Patients typically present with photophobia, nystagmus, and hyperopia, which may manifest in the first few years of life or later in childhood. Additionally, patients with SLS experience nephronophthisis, a condition that is marked by cystic kidney disease (medullary cystic kidney disease), reduced concentrating ability, and chronic tubule-interstitial nephritis. Over time, the disease typically progresses to end-stage renal disease [54, 55]. SLS is inherited as an autosomal recessive Mendelian disorder [56]. To date, mutations in 10 genes are associated with SLS including NPHP1 [57], NPHP2 [58], NPHP3 [59], NPHP4 [60], NPHP5/IQCB1 [61], NPHP6/CEP290 [62, 63], NPHP10/SDCCAG8 [64], NPHP13/WRD19 [65], NPHP15/CEP164 [66], TRAF3IP1 [67].

This review was carried out between November-2022 and April-2023 by following PRISMA guidelines as mentioned in Supplementary Table S1. Briefly, the inclusion criteria for considering genetic studies comprised families of Pakistani descent, exhibiting both syndromic and non-syndromic inherited retinal disorders, and articles published during the period spanning from 1999 to April-2023. A thorough literature survey was performed for this purpose using PubMed (NCBI), Google Scholar, Web of Science, and Scopus. Different key words such as inherited retinal degenerations/dystrophies, IRDs, retinitis pigmentosa (syndromic/non-syndromic), Stargardt disease, cone- and/or cone-rod dystrophy, macular degeneration, congenital stationary night blindness, leber congenital amaurosis, achromatopsia, color blindness, mutations, Pakistan, etc. were used for retrieving relevant literature. All articles that appeared during our search were further shortlisted and papers that did not fall under the purview of this review were excluded. This included articles presenting findings related to non-retinal phenotypes like cataract, age related macular dystrophy, microphthalmia, anophthalmia and sporadic cases. Data pertaining to genetic and clinical aspects of the families were extracted from all papers and recorded (and tabulated) in Microsoft (MS) excel sheet. This followed manual curation of the data using different options of the MS excel tool. Genomic nomenclature of all variants reported in this study were validated using VariantValidator [https://variantvalidator.org]. Additional features of the variants such as impact of the variations on cDNA and protein level, gene symbols, protein and transcript ID, genomic coordinates of the variation, inheritance pattern, and allele frequencies were determined using major genomic data bases (Ensemble, UCSC, HGNC, OMIM, gnomAD). All identified variants were queried in different online databases such as ClinVar, HGMD and Varsome to check their clinical significance. ACMG verdicts about the variants were retrieved from Varsome database. Retinal information network (RetNet) was used to calculate number of genes associated with each IRDs type. All missense variants were evaluated for their predicted pathogenicity using different in-silico tools, namely, CADD, DANN, LRT, Mutation Assessor, Mutation Taster, Mutpred, PolyPhen-2, PROVEAN, and SIFT.

Demographic and clinical features of IRDs

This review paper focused on a total of 126 published research articles documenting IRDs from Pakistani population between 1999 and April-2023 (Fig. 1). All articles were thoroughly checked to infer different features such as ethnic affiliation of the patients, parental consanguinity, zygosity of the identified alleles, mutation types/molecular impact of the alleles, inheritance pattern, and disease type (Table 1). Collectively, highest number of IRDs cases were reported from Punjab province (32%), followed by Khyber Pakhtunkhwa (14%), Sindh (1%), Baluchistan (1%), and Kashmir (< 1%), while a subset (1.1%) of studies documented IRDs in Pakistani families living abroad (UK/Canada). In the remaining 50% cases, no ethnic affiliation could be inferred from the published reports. Analysis of the retrieved articles for presence/absence of parental consanguinity revealed that parents were consanguineously married in 70% of the cases, 2% non-consanguineously married while no information about parental consanguinity were available in 28% cases. Interestingly, 95% IRDs cases were found to follow autosomal recessive (AR) inheritance pattern followed by autosomal dominant (AD) (2%), X-Linked (1%) pattern. The authors did not provided information on the inheritance pattern for ~ 2% cases. Variants in these 2% cases were found in genes which can cause both AD and AR inheritance pattern (as per OMIM database). While 77% cases were classified as non-syndromic, the remaining 23% were syndromic cases (Table 1). Syndromic IRDs included Alström syndrome (AS) (~ 1%), BBS (8%), Cohen syndrome (COH) (~ 1%), JBTS (2%), MKS (1%), Retinal dystrophy with microvillus inclusion disease (RDMVID) (< 1%), SLSN (1%), USH (8%), Zellweger syndrome (ZS) (< 1%). Non-syndromic cases comprised RP (41%), LCA (14%), CSNB (6%), CRD (4%), RD (3%), Achromatopsia (2%), STGD (2%), Fundus Albipunctatus (FA) (1%), Hypotrichosis juvenile macular dystrophy HJMD (1%), FA/CSNB (~ 1%), LCA/EORD (~ 1%), MD (~ 1%), Retinitis punctata albescens (RPA) (~ 1%), Aniridia (< 1%), Anterior segment dysgenesis (ASD) (< 1%), Early onset retinal dystrophy (EORD) (< 1%), Choroideremia (CHM) (< 1%), Retinoschisis (RS) (< 1%) (Fig. 2).

Table 1
Characteristics of the identified 359 variants reported in Pakistani IRDs families between 1999 and April 2023
Characteristics	No.	%
Population (n = 359)
N.D	181	50.42
Punjab	116	32.31
Khyber Pakhtunkhwa	50	13.93
Britishi Pakistani	3	0.84
Sindh	4	1.11
Balochistan	3	0.84
Canadian Pakistani	1	0.28
Kashmir	1	0.28
Parental consanguinity (n = 359)
Yes	252	70.19
N.D	99	27.58
No	8	2.23
Clinical Diagnosis (n = 359)
Non-Syndromic	278	77.44
Syndromic	81	22.56
Zygosity (n = 359)
Homozygous	325	90.53
N.D	24	6.69
Heterozygous	7	1.95
Hemizygous	3	0.84
Mutation Type (n = 359)
Missense	155	43.18
Indels/Frameshift	93	25.91
Nonsense	67	18.66
Splicing	43	11.97
Synonymous	1	0.28
Inheritance pattern (n = 359)
Autosomal Dominant	6	1.7
Autosomal Recessive	343	95.5
Autosomal Dominant/Recessive	6	1.7
X-Linked	4	1.1
Missense variants (n = 116)	No.	%
ACMG classification
Benign	6	5.17
Likely Benign	2	1.72
Likely Pathogenic	31	26.72
Pathogenic	32	27.59
Uncertain Significance	45	38.79
ClinVar classification	No.	%
Benign	1	0.86
Benign/Likely Benign	4	3.45
Likely Benign	1	0.86
Conflicting	9	7.76
Likely Pathogenic	13	11.21
Pathogenic	29	25.00
Pathogenic/Likely Pathogenic	8	6.90
Uncertain Significance	15	12.93
N.D	36	31.03
Single base substitutions (n = 223)	No.	%
Synonymous	1	0.45
Missense	155	69.51
Nonsense	67	30.04
Transitions (n = 147)
Purine-Purine	65	44.22
Pyramidine-Pyramidine	82	55.78
Transversions (n = 76)
Purine-Pyramidine	43	56.58
Pyramidine-Purine	33	43.42
Base substitution types	No.	%
Transitions
C > T	62	27.80
G > A	44	19.73
A > G	21	9.42
T > C	20	8.97
Transversions
G > T	20	8.97
C > A	16	7.17
G > C	13	5.83
T > G	10	4.48
A > T	8	3.59
C > G	5	2.24
T > A	2	0.90
A > C	2	0.90

Genetic spectrum of IRDs

Various characteristics of the identified variants are shown in Table 1. A total of 359 disease-causing alleles across 89 known IRDs-associated genes were documented in the literature under the scope of this study as mentioned in supplementary Table S2. Commonly mutated genes included PDE6A (5.3%), TULP1 (4.7%), RP1 (4.45%), RPE65 (4.45%), CDH23 (3.34%), CRB1 (3.34%), GUCY2D (3.34%), LCA5 (3%), RGRIP1 (3%), USH2A (3%), AIPL1 (2.78%), RDH5 (2.78%) PDE6B (2.78%) (Fig. 3). On the contrary, least frequently mutated genes, categorized as “Others”, were ARL13B, ARL3, ASRGL1, BEST1, CC2D2A, CHM, DRAM2, FOXE3, IFT43, IMPG2, MKKS, MKS1, NPHP4, NR2E3, NYX, PAX6, PDE6H, PEX6, PRCD, PRPF3, RBP3, RPGR, RS1, SLC6A6, SNRNP200, STX3 and TCTN2 (each reported only once in Pakistani population so far) (Fig. 3). Of the total 359 disease-causing alleles, 90.5% alleles were found in a homozygous state, 1.9% in heterozygous state, and ~ 0.9% were in hemizygous state; however, zygosity of the left over 6.7% alleles were not reported in the published reports (Table 1). Based on their predicted impact on protein, alleles were classified as missense, nonsense, frameshift, splicing, and synonymous with their respective frequencies of 43.2%, 18.6%, 25.9%, 12%, and 0.3% (Table 1). Of the total alleles (n = 359), 62.1% (223 alleles) were classified as single nucleotide variants (SNVs). Of the SNVs, 147 were transitions (Purine – Purine, n = 65), (Pyramidine – Pyramidine, n = 82) and 76 were transversions (Purine – Pyramidine, n = 43), (Pyramidine – Purine, n = 33) (Table 1). A C > T was the most frequent (~ 28%) transition followed by G > A (~ 20%), A > G (9%), and T > C (9%). Similarly, G > T (9%) was the mostly frequent transversion followed by C > A (7%), G > C (~ 6%), T > G (4%), A > T (~ 4%), C > G (2%), T > A (~ 1%) and A > C (~ 1%) (Table 1 and Fig. 4). Using ACMG guidelines, all reported alleles were re-evaluated for their clinical significance. Collectively, ‘pathogenic’ variants were found to be 41% followed by ‘likely pathogenic’ (~ 31%), ‘variants of uncertain significance (19%), ‘benign’ (~ 2%) and ‘likely benign’ (< 1%). Of the total, no ACMG criterion could be established for 6% alleles (Supplementary Table S2). Further, all missense variants (n = 116) were classified as per ACMG guidelines. Of the total missense, ACMG predicted 45 alleles as VUS, 32 as pathogenic, 31 as likely pathogenic, 6 as benign and 2 as likely benign. ClinVar showed 29 variants as pathogenic, 15 as VUS, 13 as likely pathogenic, 9 as conflicting, 8 as pathogenic/likely pathogenic, 6 as benign/likely benign. Thirty-six alleles were not found on ClinVar database (Table 1). Eight variants were classified as benign/likely benign as shown in Table 3. Nine in-silico tools were used to calculate predicted pathogenicity scores/verdict for the missense variants. These included CADD, DANN, LRT, Mutation assessor, Mutation taster, Mutation prediction, Polyphen-2, PROVEAN, and SIFT with prediction of each tool shown in (Table 2).

Table 2
*In-silico* predictions of the identified 116 missense variants reported in Pakistani families
Gene	Transcript ID	cDNA	CADD	DANN	LRT	MA	MT	MutPred	PolyPhen-2	PROVEAN	SIFT	ACMG	ClinVar
USH2A	NM_206933.4	c.7334C > T	32	VUS	B	VUS	B	VUS	PD	VUS	VUS	B	B
RP1	NM_006269.2	c.1118C > T	9.092	B	B	VUS	B	n.a	B	B	VUS	B	B/LB
SEMA4A	NM_022367.4	c.2138G > A	21.3	VUS	B	B	B	n.a	B	B	B	B	B/LB
RPGRIP1	NM_020366.4	c.1639G > T	22.5	VUS	B	B	B	n.a	PD	B	B	B	B/LB
CRB1	NM_201253.3	c.1459T > C	22.6	VUS	n.a	VUS	VUS	VUS	PD	P	VUS	VUS	B/LB
NR2E3	NM_014249.4	c.227G > A	16.07	B	B	B	n.a	n.a	PD	n.a	n.a	LP	CFL
BEST1	NM_004183.4	c.418C > G	22.8	VUS	B	P	VUS	P	PD	B	VUS	LP	CFL
PDE6A	NM_000440.3	c.304C > A	23.6	VUS	P	VUS	B	n.a	PD	VUS	B	P	CFL
CNGA3	NM_001298.3	c.822G > T	24.1	VUS	P	P	VUS	P	PD	P	P	P	CFL
PRPF3	NM_004698.4	c.1481C > T	29.4	VUS	P	P	VUS	P	PD	P	P	P	CFL
IFT43	NM_001102564.3	c.100G > A	22.6	VUS	B	B	B	n.a	PD	VUS	VUS	VUS	CFL
BBS1	NM_024649.5	c.442G > A	22.7	VUS	n.a	VUS	VUS	n.a	PD	VUS	B	VUS	CFL
CERKL	NM_201548.5	c.316C > A	26.5	VUS	VUS	VUS	VUS	P	PD	VUS	B	VUS	CFL
ABCA4	NM_000350.3	c.2023G > A	26.9	VUS	P	P	VUS	n.a	PD	B	P	VUS	CFL
ALMS1	NM_001378454.1	c.5242A > G	17.8	VUS	n.a	n.a	VUS	n.a	n.a	n.a	n.a	B	LB
CNGA3	NM_001298.3	c.827A > G	24.8	VUS	P	P	VUS	P	PD	P	P	LP	LP
ABCA4	NM_000350.3	c.91T > C	27.7	VUS	B	P	VUS	P	PD	P	P	LP	LP
RPE65	NM_000329.3	c.119G > A	28.1	VUS	P	P	VUS	P	PD	P	P	LP	LP
SLC6A6	NM_003043.6	c.1196G > T	33	VUS	P	P	VUS	P	PD	n.a	n.a	LP	LP
FOXE3	NM_012186.3	c.289A > G	23.7	VUS	B	P	VUS	P	PD	B	P	P	LP
RHO	NM_000539.3	c.448G > A	25.3	P	VUS	VUS	VUS	P	PD	B	VUS	P	LP
RLBP1	NM_000326.5	c.346G > C	33	VUS	P	B	VUS	VUS	PD	B	B	P	LP
AIPL1	NM_014336.5	c.773G > C	15.35	B	B	B	VUS	VUS	PD	VUS	B	VUS	LP
PDE6B	NM_001145292.2	c.938C > T	24.3	VUS	P	B	VUS	VUS	B	B	B	VUS	LP
CEP290	NM_025114.4	c.148C > T	26.7	VUS	VUS	B	VUS	B	PD	B	VUS	VUS	LP
CLRN1	NM_174878.3	c.461T > G	27	B	P	VUS	VUS	VUS	PD	P	VUS	VUS	LP
DHX38	NM_014003.4	c.971G > A	29.1	P	VUS	P	VUS	B	PD	VUS	VUS	VUS	LP
TULP1	NM_003322.6	c.1561C > T	32	VUS	P	P	VUS	P	PD	P	P	VUS	LP
SNRNP200	NM_014014.5	c.3269G > A	32	P	P	P	VUS	P	PD	VUS	P	LP	P
GUCY2D	NM_000180.4	c.2302C > T	32	P	VUS	P	B	n.a	PD	P	P	P	P
CLRN1	NM_174878.3	c.92C > T	23.9	VUS	VUS	B	VUS	VUS	PD	VUS	VUS	LP	P
RDH5	NM_002905.5	c.536A > G	24.5	VUS	P	P	VUS	P	PD	VUS	VUS	LP	P
RDH12	NM_152443.3	c.619A > G	25.5	VUS	P	P	VUS	P	PD	P	VUS	LP	P
PDE6B	NM_000283.4	c.1160C > T	25.6	VUS	P	P	VUS	P	PD	P	P	LP	P
SEMA4A	NM_022367.4	c.1049T > G	26.1	VUS	VUS	P	VUS	P	PD	P	P	LP	P
ARL13B	NM_001174150.2	c.236G > A	31	P	VUS	VUS	VUS	P	PD	VUS	P	LP	P
RPE65	NM_000329.3	c.1087C > A	22.7	VUS	VUS	VUS	VUS	P	B	B	B	P	P
CRB1	NM_201253.3	c.2536G > A	22.8	VUS	n.a	P	VUS	P	PD	P	P	P	P
NMNAT1	NM_022787.4	c.25G > A	23.6	VUS	B	P	B	VUS	PD	B	P	P	P
CNGA3	NM_001298.3	c.1306C > T	24	VUS	P	P	VUS	n.a	PD	P	P	P	P
PRCD	NM_001077620.3	c.2T > C	24.2	VUS	VUS	n.a	VUS	P	n.a	B	VUS	P	P
TMEM67	NM_153704.6	c.1127A > C	26	VUS	VUS	VUS	VUS	VUS	PD	VUS	VUS	P	P
RDH12	NM_152443.3	c.609C > A	27.1	VUS	P	P	VUS	P	PD	P	P	P	P
TULP1	NM_003322.6	c.1466A > G	28.2	VUS	P	P	VUS	P	PD	VUS	P	P	P
ABCA4	NM_000350.3	c.5882G > A	28.4	VUS	P	B	VUS	n.a	PD	P	P	P	P
GRM6	NM_000843.4	c.2267G > A	22.3	VUS	n.a	VUS	B	P	B	VUS	B	VUS	P
CLCC1	NM_001377458.1	c.75C > A	23.6	VUS	P	P	VUS	P	PD	VUS	P	VUS	P
ABCA4	NM_000350.3	c.5243G > A	25.1	VUS	B	VUS	B	VUS	PD	VUS	B	VUS	P
RPGRIP1	NM_020366.4	c.2480G > T	25.1	VUS	VUS	VUS	VUS	P	PD	P	VUS	VUS	P
ARL6/BBS3	NM_001278293.3	c.281T > C	25.8	VUS	P	P	VUS	P	n.a	VUS	P	LP	P
ARL3	NM_004311.4	c.296G > T	32	VUS	P	P	VUS	P	PD	P	P	LP	P
GNAT1	NM_144499.3	c.386A > G	32	VUS	P	P	VUS	P	PD	P	P	LP	P
BBS5	NM_152384.3	c.2T > A	24.2	VUS	VUS	n.a	VUS	P	n.a	B	VUS	P	P
IMPDH1	NM_000883.4	c.931G > A	25.6	VUS	P	n.a	VUS	P	PD	P	VUS	P	P
CNGB1	NM_001297.5	c.2284C > T	29.4	P	P	P	VUS	n.a	PD	P	P	P	P
RPE65	NM_000329.3	c.131G > A	31	P	VUS	P	VUS	P	PD	VUS	P	P	P
TULP1	NM_003322.6	c.1445G > A	31	P	P	P	VUS	n.a	PD	VUS	P	P	P
CRB1	NM_201253.3	c.2234C > T	23.1	VUS	n.a	P	VUS	n.a	PD	P	P	P	P/LP
CNGA3	NM_001298.3	c.847C > T	26.5	VUS	P	P	VUS	P	PD	P	P	P	P/LP
CNGA3	NM_001298.3	c.955T > C	26.6	VUS	P	P	VUS	P	PD	P	P	P	P/LP
ABCA4	NM_000350.3	c.214G > A	27.6	P	VUS	P	VUS	n.a	PD	P	P	P	P/LP
USH1G/SANS	NM_173477.5	c.1373A > T	28.7	VUS	P	P	VUS	P	PD	n.a	n.a	P	P/LP
PDE6B	NM_000283.4	c.1655G > A	29.3	P	P	P	VUS	P	PD	VUS	P	P	P/LP
RDH12	NM_152443.3	c.506G > A	31	P	P	VUS	VUS	P	PD	VUS	P	P	P/LP
PDE6A	NM_000440.3	c.1630C > T	32	P	VUS	VUS	B	n.a	PD	P	P	P	P/LP
ZNF513	NM_144631.6	c.1015T > C	23.8	VUS	VUS	B	VUS	VUS	PD	P	VUS	B	VUS
SEMA4A	NM_022367.4	c.1033G > C	24.4	VUS	VUS	P	VUS	P	PD	VUS	VUS	LP	VUS
BBS12	NM_152618.3	c.1616G > T	25.4	VUS	VUS	VUS	VUS	P	PD	P	VUS	LP	VUS
RPE65	NM_000329.3	c.782T > C	28.6	VUS	P	P	VUS	P	PD	P	P	LP	VUS
GUCY2D	NM_000180.4	c.2384G > A	31	P	VUS	P	B	n.a	PD	VUS	P	LP	VUS
PEX6	NM_000287.4	c.2626C > T	32	P	P	P	VUS	n.a	PD	P	VUS	LP	VUS
RPE65	NM_000329.3	c.751G > T	32	VUS	P	P	VUS	P	PD	VUS	P	LP	VUS
RP1	NM_006269.2	c.2005G > A	1.173	B	B	B	VUS	n.a	B	B	B	VUS	VUS
FAM161A	NM_001201543.2	c.1139G > T	18.53	VUS	B	VUS	VUS	P	PD	P	VUS	VUS	VUS
NMNAT1	NM_022787.4	c.547C > T	22.7	VUS	B	P	B	VUS	PD	VUS	VUS	VUS	VUS
GRM6	NM_000843.4	c.824G > A	23.7	VUS	n.a	VUS	VUS	VUS	PD	VUS	B	VUS	VUS
EYS	NM_001142800.2	c.7187G > C	25.7	VUS	VUS	P	B	P	PD	VUS	P	VUS	VUS
DHX38	NM_014003.4	c.995G > A	25.8	VUS	VUS	VUS	VUS	B	PD	P	B	VUS	VUS
RAX2	NM_001319074.4	c.236G > A	29.7	VUS	B	P	VUS	P	n.a	n.a	n.a	VUS	VUS
AIPL1	NM_014336.5	c.465G > T	35	VUS	B	B	VUS	VUS	PD	VUS	VUS	VUS	VUS
RAX2	NM_001319074.4	c.374G > A	1.497	B	B	B	VUS	B	n.a	n.a	n.a	LB	N.A
EYS	NM_001142800.2	c.8299A > T	23.4	VUS	B	VUS	B	VUS	PD	B	B	LB	N.A
CRB1	NM_201253.3	c.433T > C	24.6	VUS	n.a	P	VUS	P	PD	P	P	LP	N.A
GUCY2D	NM_000180.4	c.2189T > C	24.8	VUS	VUS	P	B	P	PD	P	P	LP	N.A
ASRGL1	NM_001083926.2	c.532G > A	25.6	P	P	P	VUS	P	PD	P	P	LP	N.A
TULP1	NM_003322.6	c.1274T > C	26.4	VUS	VUS	P	VUS	P	PD	P	P	LP	N.A
CNGA3	NM_001298.3	c.991G > C	27.3	P	P	P	VUS	P	PD	P	P	LP	N.A
RPE65	NM_000329.3	c.179T > C	28.6	VUS	P	VUS	VUS	P	PD	VUS	P	LP	N.A
RDH5	NM_002905.5	c.319G > C	28.8	P	P	VUS	VUS	P	PD	P	P	LP	N.A
LRAT	NM_004744.5	c.196G > C	31	VUS	P	P	VUS	P	PD	P	P	LP	N.A
CRB1	NM_201253.3	c.3101G > C	25.5	VUS	n.a	P	VUS	VUS	n.a	P	P	LP	N.A
CRB1	NM_201253.3	c.3962G > C	25.5	P	n.a	P	VUS	P	PD	P	P	P	N.A
USH2A	NM_206933.4	c.12523T > G	29.5	VUS	B	P	VUS	P	PD	P	P	P	N.A
GUCY2D	NM_000180.4	c.2384G > T	31	VUS	VUS	P	B	P	PD	P	P	P	N.A
CRB1	NM_201253.3	c.3347T > C	9.398	B	n.a	VUS	VUS	VUS	B	B	B	VUS	N.A
RDH5	NM_002905.5	c.668A > C	22.1	VUS	B	VUS	B	VUS	PD	VUS	B	VUS	N.A
CRB1	NM_201253.3	c.2966T > C	22.2	VUS	n.a	VUS	VUS	P	PD	VUS	VUS	VUS	N.A
GUCY2D	NM_000180.4	c.530G > C	22.7	VUS	B	VUS	VUS	P	PD	VUS	VUS	VUS	N.A
AIPL1	NM_014336.5	c.116C > A	23.4	B	P	P	VUS	P	PD	P	P	VUS	N.A
TULP1	NM_003322.6	c.1307C > G	23.4	VUS	VUS	B	VUS	P	B	P	VUS	VUS	N.A
IMPDH1	NM_000883.4	c.676G > A	23.6	VUS	P	n.a	VUS	P	B	P	B	VUS	N.A
RDH5	NM_002905.5	c.602C > T	23.6	VUS	VUS	P	B	VUS	PD	VUS	VUS	VUS	N.A
BBS2	NM_031885.5	c.443A > T	23.8	VUS	VUS	n.a	B	P	PD	VUS	P	VUS	N.A
CRB1	NM_201253.3	c.3296C > A	24.3	VUS	n.a	VUS	VUS	VUS	PD	VUS	VUS	VUS	N.A
RPGRIP1	NM_020366.4	c.2656C > T	24.7	VUS	VUS	P	VUS	B	PD	VUS	VUS	VUS	N.A
MKKS	NM_170784.3	c.280T > C	25	VUS	VUS	P	VUS	P	PD	VUS	B	VUS	N.A
TULP1	NM_003322.6	c.1138A > G	25.2	VUS	P	VUS	VUS	P	B	P	VUS	VUS	N.A
LCA5	NM_001122769.3	c.652C > G	25.3	VUS	VUS	VUS	B	B	PD	P	P	VUS	N.A
BBS12	NM_152618.3	c.1589T > C	26	VUS	VUS	VUS	VUS	P	PD	P	P	VUS	N.A
GUCY2D	NM_000180.4	c.917A > T	26	VUS	VUS	VUS	VUS	P	PD	P	P	VUS	N.A
CNGA3	NM_001298.3	c.952G > A	26.5	VUS	P	P	VUS	P	PD	VUS	VUS	VUS	N.A
CDH23	NM_022124.6	c.7198C > T	27	P	VUS	P	VUS	VUS	PD	P	P	VUS	N.A
RDH5	NM_002905.5	c.758T > G	27.2	B	P	VUS	VUS	VUS	PD	VUS	B	VUS	N.A
CDH23	NM_022124.6	c.8150A > G	29	VUS	P	P	VUS	P	PD	P	P	VUS	N.A
GUCY2D	NM_000180.4	c.582G > C	29.8	VUS	B	VUS	VUS	P	PD	P	P	VUS	N.A
ADAM9	NM_003816.3	c.1144T > G	32	VUS	P	P	VUS	P	PD	P	P	VUS	N.A
MT; Mutation taster, MA; Mutation assessor, LRT; Likelihood ratio test, SIFT; Sorting intolerant from tolerant, ACMG; The American college of medical genetics and genomics, B; Benign, LB; Likely benign, B/LB; Benign/Likely benign, P; Pathogenic, LP; Likely pathogenic, P/LP; Pathogenic/Likely pathogenic, PD; Probably/Possibly damaging, VUS; Variant of uncertain significance, CFL; Conflicting, NA; Not available.

Table 3
List of variants classified as ‘benign or Likely benign’ by the ACMG guidelines
	cDNA change	Protein change	gnomAD MAF	Disease	Population	Consanguinity	Zygosity	ACMG
SEMA4A	c.2138G > A	p.(Arg713Gln)	0.03651	adRP	N.D	No	Heterozygous	Benign
USH2A	c.7334C > T	p.(Ser2445Phe)	0.000841	arUSH2	KPK	No	Homozygous	Benign
RPGRIP1	c.1639G > T	p.(Ala547Ser)	0.2038	arCRD	N.D	Yes	Homozygous	Benign
RP1	c.1118C > T	p.(Thr373Ile)	0.01215	arRP	N.D	Yes	Homozygous	Benign
ZNF513	c.1015T > C	p.(Cys339Arg)	0.0001668	arRP	Punjab	Yes	Homozygous	Benign
ALMS1	c.5242A > G	p.(Lys1748Glu)	NA	arAS	Punjab	Yes	Homozygous	Benign
RAX2	c.374G > A	p.(Gly125Glu)	NA	arRD	Punjab	yes	Homozygous	Likely Benign
RAX2	c.8299A > T	p.(Thr2767Ser)	NA	arRP	Punjab	yes	Homozygous	Likely Benign

This study provides an overview of the existing clinical and genetic aspects of IRDs in Pakistani population. Based on the published reports, majority of the IRDs families reported from Pakistan were originated from two ethnic populations i.e. Punjab and Khyber Pakhtunkhwa provinces thus leaving Sindh, Baluchistan and Gilgit-Baltistan as underrepresented populations in the medical literature. Consistent with the traditional practice of endogamy in the country [68–70], over 70% IRDs cases published so far were found among children whose parents were consanguineously married. Consequently, recessively inherited IRDs were disproportionately high (95%) in the country as opposed to dominant cases (5%). These findings suggest that consanguinity can greatly leverage while identifying disease-causing mutations in recessively inherited Mendelian disorders using homozygosity mapping in endogamous populations as explained earlier [71, 72].

In this review, a total of 278 genomic variants across 89 IRD-associated genes were retrieved from a total of 126 published research article. While ~ 70% of the above IRD-associated genes were mutated two or-more times, around 30% of them were mutated only once in the Pakistani IRDs patients. Our analysis revealed PDE6A as the top most frequently mutated gene followed by TULP1, RP1, and RPE65 genes, collectively, contributing towards approximately 19% IRDs cases in Pakistan. Previous literature suggests that at least 12 IRDs-associated genes have been first identified/reported in Pakistani families [73, 74]. Of the total retrieved variants detected in IRDs families of Pakistani origin, ~ 80% were considered as ‘rare’ since they were reported only once from the Pakistani population. The remainder ~ 20% variants were observed at least twice from Pakistani population, hence considered as ‘recurrent’ alleles. Of the recurrent alleles, a frameshift mutation in LCA5 gene (NM_001122769.3:c.1151delC;p.Pro384GlnfsTer18) was independently reported seven times [75–81], and thus considered as the most commonly reported allele so far. The second most frequent IRDs associated allele was a missense substitution in TULP1 gene (NM_003322.6:c.1138A > G:p.Thr380Ala) which was reported by five independent studies [78–80, 82, 83]. In addition to the likelihood that these alleles constitute hotspot mutations, frequent occurrence of these alleles in multiple families of Pakistani origin might indicate a founder effect in the society.

In-silico study of the identified missense variants (n = 116) revealed that eight alleles were eligible to be classified as benign/likely benign consistently by the ACMG and ClinVar system, as well as by majority of the online in-silico predictors. These included SEMA4A (p.Arg713Gln) [84], USH2A (p.Ser2445Phe) [85], RPGRIP1 (p.Ala547Ser) [86], RP1 (p.Thr373Ile) [87], ZNF513 (p.Cys339Arg) [7], ALMS1 (p.Lys1748Glu) [77], RAX2 (p.Gly125Glu) [88], and EYS (p.Thr2767Ser) [89]. Our CADD score analysis of missense variants revealed RP1 (c.2005G > A; p.Ala669Thr), and RAX2 (c.374G > A; p.Gly125Glu) to show lowest CADD-PHRED scores of 1.173 and 1.497, respectively while AIPL1 (c.465G > T; p.Gln155His) appeared with a highest CADD-PHRED score of 35. Though our in-silico findings about these alleles are not conclusive, we recommend further investigation of these variants to fully understand their functional impact on protein and/or their phenotypic consequences if any.

Furthermore, we have found that RP is the most genetically heterogeneous disorder among IRDs in Pakistani population as mutations in 37 different IRDs associated genes were identified. Approximately, 41% of IRDs cases were classified as RP. Our findings, of RP as the most leading IRD type in Pakistani population, align with previous studies suggesting RP as the most frequently reported form of visual impairment in world populations [90–94].

Contrary to a global trend of ABCA4 gene as the most frequently IRD causing gene [92–94], we have witnessed PDE6A as the most frequently mutated gene in IRDs cohort of Pakistani origin. Nevertheless, we have found a unique genetic architecture in the Pakistani population. For example, Janecke and colleagues [95] associated a rare intestinal-retinal syndrome in a consanguineous Pakistani family with a frameshift mutation (c.372_373dup: p.(Arg125LeufsTer7) in STX3 gene. Similarly, Rafiq et al. [96] have correlated Cohen syndrome with VPS13B gene mutations in two separate Pakistani families of Baloch ethnic origin. Interestingly, as per OMIM database, disease-causing mutations in SNRNP200 gene are associated with adRP. However, Austuti et al 2018 [97] have associated SNRNP200 mutation to arRP in a Pakistani family.

This study provides a comprehensive and updated overview of IRDs in Pakistan over a period of 25 years (1999–2023). Our analysis reaffirms the fact that majority of the prevalent IRDs cases in Pakistan are recessively inherited, and are mostly appeared due to the bi-allelic inheritance of homozygous pathogenic mutations from a consanguineous parent. Prevalence of non-syndromic IRDs was disproportionately higher than syndromic IRDs (77% vs. 23%). RP, with associated mutations reported in as many as 37 genes, was the most frequently occurring IRD followed by LCA. Overall, mutations in PDE6A gene was the leading cause of IRDs in Pakistani population followed by mutations in TULP1 gene. Altogether, marked genetic and allelic and heterogeneity was observed in the Pakistani IRDs cases. In summary, Pakistani families are notable in expressing both common and rare Mendelian disorders such as Cohen syndrome, intestinal-retinal syndrome, and taurine transporter deficiency possibly due to the traditional practice of endogamy in the society.

Limitations

Since the data presented in this study were all retrieved from published reports, and further validated/curated using online databases, we foresee certain limitations in our study. For example, we do not claim causality of variants (if any) presented here as it does not fall under the purview of our study. Despite our own efforts, we do see the possibility of overlooking certain relevant literature on the subject. Incomplete information, inconsistencies or in some cases errors seen in the retrieved data may have skewed our own analysis. It is pertinent to mention here that all calculations were based on the total number of alleles (n = 359) identified so far. However, we were unfortunately unable to assess objectively the total number of families affected by these 359 alleles due to the inadequate information provided in the literature. Nevertheless, published reports emerged mostly from two provinces of Pakistan i.e. Punjab and Khyber Pakhtunkhwa. Therefore, we recommend taking care while extrapolating our findings to other Pakistani populations like Sindh, Baluchistan and Gilgit-Baltistan.

ACMG: The American College of Medical Genetics and Genomics; adRP: Autosomal Dominant Retinitis Pigmentosa; arRP: Autosomal Recessive Retinitis Pigmentosa; AS: Alström syndrome; ASD: Anterior segment dysgenesis; BBS: Bardet-Biedl syndrome; CADD: Combined Annotation Dependent Depletion; CD/CRD: Cone dystrophy or Cone rod dystrophy; CHM: Choroideremia; COH: Cohen syndrome; CSNB: Congenital Stationary Night Blindness; EORD: Early onset retinal dystrophy; FA: Fundus Albipunctatus; gnomAD: Genome aggregation database; HGMD: Human Gene Mutation Database; HJMD: Hypotrichosis juvenile macular dystrophy; IRDs: Inherited retinal degenerations; JBTS: Joubert syndrome; LCA: Leber’s congenital amaurosis; MD: Macular degeneration; MKS: Meckel Syndrome; RDMVID: Retinal dystrophy with microvillus inclusion disease; RP: Retinitis pigmentosa; RPA: Retinitis punctata albescens; RS: Retinoschisis; SIFT: Sorting Intolerant from Tolerant; SLS: Senior-Loken syndrome; STGD: Stargardt disease; USH: Usher Syndrome, and ZS: Zellweger syndrome.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare that no conflict of interest exists.

Funding

Not applicable.

Authors’ contribution

AM and AUR conceived the idea. AM and SA collected and tabulated the data. AM and AUR analyzed the data and wrote the manuscript. All authors thoroughly read and approved the final version of the manuscript.

Acknowledgments

None.

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No competing interests reported.

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A systematic review of inherited retinal dystrophies in Pakistan: Updates from 1999 to April 2023

Status:

Journal Publication

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Abstract

Background

Methods

Results

Conclusion

Figures

Introduction

Cone or Cone-Rod dystrophy (CD/CRD)

Congenital Stationary Night Blindness (CSNB)

Leber Congenital Amaurosis (LCA)

Macular degeneration (MD)

Retinitis Pigmentosa (RP)

Bardet-Biedl Syndrome

Usher Syndrome (USH)

Joubert syndrome

Senior-Loken Syndrome

Methods

Results

Demographic and clinical features of IRDs

Genetic spectrum of IRDs

Discussion

Conclusions

Limitations

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1