CASE REPORT Year : 2021  |  Volume : 28  |  Issue : 4  |  Page : 260-262  

A novel missense variant C.2571 (P.Ala857=) of the DHX38 gene in a Saudi family causes an autosomal recessive retinitis pigmentosa

Saud Al-Johani1, Abdulelah Alabdullah2, Sawsan R. Nowilaty2
1 Department of Ophthalmology, Imam Abdulrhman Bin Faisal University, Dammam, Kingdom of Saudi Arabia
2 King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia

Date of Submission04-Feb-2021Date of Acceptance14-Mar-2022Date of Web Publication30-Apr-2022

Correspondence Address:
Dr. Saud Al-Johani
Division of Ophthalmology, Imam Abdulrhman Bin Faisal Univeersity, Dammam
Kingdom of Saudi Arabia

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/meajo.meajo_40_21

   Abstract 

We present two cases of a novel missense variant mutation in the DHX38 gene, which is associated with autosomal recessive retinitis pigmentosa (RP) in two Saudi sisters who presented with poor visual acuity since childhood. On initial examination, the best-corrected visual acuity was 20/300 in both eyes for the two sisters. Fundus examination revealed widespread retinal pigmentary changes, linear peripheral hyperpigmentation clumps, bone spicules, and bilateral optic nerve drusen with bilateral macular hyperpigmentation. Spectral-domain optical coherence tomography scans reveal losses of the outer retinal layer and the presence of subretinal fibrosis and thinning of the choroid. Molecular sequencing analysis of the DHX38 exome identified a novel missense mutation of the homozygous variant c. 2571 (p. Ala857=), which co-segregates with the autosomal recessive RP gene that encodes the premRNA splicing factor, PRP16. The aim of this report is to describe the clinical feature associated with this variant and to provide additional evidence that DHX38 is involved in RP. To the best of our knowledge, this variant has not been described in the literature.

Keywords: Gene mutation, DHX38, renitis pigmentosa

How to cite this article:
Al-Johani S, Alabdullah A, Nowilaty SR. A novel missense variant C.2571 (P.Ala857=) of the DHX38 gene in a Saudi family causes an autosomal recessive retinitis pigmentosa. Middle East Afr J Ophthalmol 2021;28:260-2
How to cite this URL:
Al-Johani S, Alabdullah A, Nowilaty SR. A novel missense variant C.2571 (P.Ala857=) of the DHX38 gene in a Saudi family causes an autosomal recessive retinitis pigmentosa. Middle East Afr J Ophthalmol [serial online] 2021 [cited 2022 Apr 30];28:260-2. Available from: http://www.meajo.org/text.asp?2021/28/4/260/344447    Introduction 

Retinitis pigmentosa (RP) (OMIM 268000) is a group of inherited ocular diseases that affects 1 in 3000–5000 individuals. RP manifests as the progressive degeneration of retinal cells.[1] The symptoms of RP are generally progressive, commonly starting as night blindness, progressing to a narrowing of the visual fields leading to tunnel vision. Unfortunately, many individuals become completely blind.

There is considerable genetic heterogeneity in the cause of RP. More than 90 genes have been mapped to autosomal-recessive RP, a very rare form of the disease that accounts for <1% of all RP. Particular genes are implicated in many cases, with 2%–5% of all cases involving RP25, PDE6A, RPE65, and PDE6B.[1],[2] Two studies have recently proposed DHX38 as a gene that can be involved in arRP.[3],[4]

The aim of this report is to describe the clinical features associated with this variant and to provide additional evidence that DHX38 is involved in RP. To the best of our knowledge, this variant has not been described in the literature (HGMD 2021.1).

   Case Report 

A consanguineous union between two first-degree cousins resulted in five offspring (one boy and four girls), of which two of the daughters (sisters) are affected. The first case is 23 years old and the second case is 17 years old. Both sisters have complained of a progressive bilateral loss of night vision, which started when they were each 4 years old. No other systemic diseases are identified. On examination, the best-corrected visual acuity (BCVA) was 20/300 in both eyes wearing refraction + 3.00 diopter. The anterior segment examination was unremarkable; however, dilated fundus examinations showed widespread changes to the retinal pigmentation, linear peripheral hyperpigmentation clumps, bone spicules, and bilateral optic nerve drusen with bilateral macular hyperpigmentation [Figure 1] and [Figure 2]. Spectral-domain optical coherence tomography scans (Heidelberg Engineering, Inc., Heidelberg, Germany) reveal a loss of the outer retinal layer and the presence of subretinal fibrosis and thinning of the choroid. An electroretinogram shows nonrecordable scotopic and severely reduced photopic responses.

Figure 1: Multimodal retinal imaging in a 23 year-old female patients with the c. 2571 (p.Ala857=) in DHX38. Top: Widefield imaging shows widespread changes to the retinal pigmentation, linear peripheral hyperpigmentation clumps, bone spicules, and bilateral optic nerve drusen with bilateral macular hyperpigmentation. Middle: Transfoveal optical coherence tomography scans show loss of the outer retinal layer and the presence of subretinal fibrosis and thinning of the choroid. Bottom: fundus autofluorescence shows bilateral optic nerve drusen

Click here to view

Figure 2: Multimodal retinal imaging 17-year-old female patients with the c. 2571 (p.Ala857=) in DHX38. Top: Widefield imaging shows widespread changes to the retinal pigmentation, linear peripheral hyperpigmentation clumps, bone spicules, and bilateral optic nerve drusen with bilateral macular hyperpigmentation. Middle: Transfoveal optical coherence tomography scans show loss of the outer retinal layer and the presence of subretinal fibrosis and thinning of the choroid. Bottom: fundus autofluorescence shows bilateral optic nerve drusen

Click here to view

Whole exome sequencing analysis was conducted. More than 20,000 genes of the patients DNA were enriched and sequenced. The exome data were filtered, and recessive genes, X-chromosome-linked, and dominant inherited disease targets were examined. A novel missense mutation was observed in the homozygous variant c. 2571 (p. Ala857=) in DHX38 (OMIM: 605584), which co-segregates with the autosomal-recessive RP gene that encodes the premRNA splicing factor PRP16.

   Discussion 

In this report, we describe a novel missense mutation variant c.2571C>T; p.(Ala857=) in DHX38 in two sisters from a Saudi family. The novel autosomal-recessive RP variant was identified using whole exam sequencing. The Genome Aggregation Database (gnomAD) shows minor allele frequency of 0.0017%, which most likely is associated with the autosomal-recessive RP. Moreover, the presence of this missense in the two sisters makes it more likely to be pathogenic for autosomal-recessive RP. This is the third autosomal-recessive RP variant in DHX38 to be reported.[3],[4]

Ajmal et al. report a missense variant, c.995G>A; p.(Gly332Asp) in DHX38, in a consanguineous Pakistani family. They presented with poor visual acuity since childhood progressed to no light perception. The ophthalmic examination of the revealed severely attenuated retinal vessels throughout the entire fundus. The maculae of both eyes were severely affected showing unusually prominent and deep macular colobomas devoid of neuroretinal tissue.[3] With the exception of our patients having BCVA (20/300) and optic nerve drusen, the clinical features presented in our patients are consistent with those reported by Ajmal et al.[3] Another missense DHX38 variant c. 971G>A, p.(Arg324Gln) has been reported by Latif et al. in early-onset autosomal-recessive RP in a Pakistani family.[4]

The RNA-dependent ATPase, PRP16, is a member of the subfamily of DEAH box proteins that is encoded by DHX38. Among the various essential cell processes that involve DEAH box proteins are secondary structure modifications of RNA, splicing of premRNA splicing, and construction of the spliceosome.[5] In the second stage of splicing, PRP16 interacts with the spliceosome. The effect of PRP16 upon the structure of the spliceosome has been confirmed by cryogenic electron microscopy; this shows that following the first catalytic stage, PRP 16 step mediates the reorganization of a number of protein domains and RNA. PRP16 causes a conformational change, in which the branched intron shifts away from the catalytic center; this is considered essential for splicing to be reliable.[6]

The sequencing of exomes has accelerated in recent years; the process is incomplete, with more than 10% of inherited retinal disease (IRD)-associated exons still to be sequenced.[4] This presents the potential for previously undetected IRD-associated genes to be identified. Furthermore, it is probable that some sequences were overlooked because of technological limitations; these may be picked up as sequencing technology becomes more advanced.

According to Zeitz et al., the genes responsible for between 30% and 50% of IRDs have yet to be determined.[7] Possible explanations for such cases might be unique gene flaws, genetic deletions or duplications, or intron or promoter region variations. Another potential mechanism that could contribute to protein dysfunction is the presence of identical variants becoming involved in gene splicing or regulating.

Segregation analysis was not done for the family members which are considered to be a limitation to our study.

To understand the pathogenicity of DHX38 variants better, there is a need for more research to be conducted with the aim of identifying other autosomal-recessive RP families associated with the gene. The effects of such variants may be established in cell systems and animal model studies.

In conclusion, we have determined an association between the autosomal-recessive RP phenotype expressed in two Saudi sisters and a unique missense variant in DHX38. The observed evidence supports the postulated involvement of DHX38 in RP. A review of the literature indicates, this variant has not been reported previously. With further research, the molecular mechanisms behind severe early-onset RP in this and other families may be revealed. Moreover, additional research is required to characterize fully the mechanisms by which spliceosome components lead to retinal dystrophy.

Patient consent

This case report adheres to the tenants of the declaration of Helsinki. Ethical approval was obtained from the IRB of King Khaled Eye Specialist Hospital. Consent for genetic testing and conduction of the study was obtained from both patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

   References 
1.Ali MU, Rahman MS, Cao J, Yuan PX. Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario. 3 Biotech 2017;7:251.  
    2.Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F, et al. Retinitis pigmentosa: Genes and disease mechanisms. Curr Genomics2011;12:238-49.  
    3.Ajmal M, Khan MI, Neveling K, Khan YM, Azam M, Waheed NK, et al. A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma. J Med Genet 2014;51:444-8.  
    4.Latif Z, Chakchouk I, Schrauwen I, Lee K, Santos-Cortez RL, Abbe I, et al. Confirmation of the role of DHX38 in the etiology of early-onset retinitis pigmentosa. Invest Ophthalmol Vis Sci 2018;59:4552-7.  
    5.Bleichert F, Baserga SJ. The long unwinding road of RNA helicases. Mol Cell 2007;27:339-52.  
    6.Bertram K, Agafonov DE, Liu WT, Dybkov O, Will CL, Hartmuth K, et al. Cryo-EM structure of a human spliceosome activated for step 2 of splicing. Nature 2017;542:318-23.  
    7.Zeitz C, Michiels C, Neuillé M, Friedburg C, Condroyer C, Boyard F, et al. Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders. Hum Mutat 2019;40:765-87.  
    
  [Figure 1], [Figure 2]