Saudi Patient Research Articles

Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia

Background & Objective: Autosomal recessive cerebellar ataxias (ARCA) are rare heterogenous neurodegenerative disorders characterized by degeneration of the cerebellum and spinal cord with an early onset before the age of 20 years. PMPCA (MIM: 613036), is a key enzyme in mitochondrial protein processing which is critical for cell survival and growth. Our objective was to investigate Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA) mutations linked with Spinocerebellar ataxia, autosomal recessive 2 (SCAR2). Method: In the current study, Whole Exome Sequencing (WES) was done followed by Sanger sequencing for the validation of the WES results. Results: WES results identified a novel homozygous variant, NM_015160.2: c.802C>T p.(Arg268Trp) in PMPCA gene. Mutation in this gene leads to progressive cerebellar ataxia with fine motor skills difficulties, intentional tremors, slow slurred speech and learning difficulties in a 12-year-old Saudi patient. WES results were further validated by Sanger sequencing technique. Conclusions: Identified phenotype in our case was similar as previously described for SCAR2 related conditions. To our knowledge, this is the first reported mutation in PMPCA gene leading to SCAR2 in Saudi Arabia. These findings will enrich the scarce literature, further provide a new insight on the role of PMPCA gene-related disorders leading to SCAR2 and expand the disease concept. In addition, this will help to establish a database for the disease and its causative factors will further help in controlling diseases resulting from consanguinity in Saudi population. doi: https://doi.org/10.12669/pjms.40.10.10474 How to cite this: Bagabir HA, Abdulkareem AA, Muthaffar OY, Shirah BH, Naseer MI. Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia. Pak J Med Sci. 2024;40(10):2243-2250. doi: https://doi.org/10.12669/pjms.40.10.10474 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report

BackgroundHelsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis.Case presentationWe report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition.ConclusionsClinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

Systematic review and meta-analysis on antimicrobial resistance and drug resistance in Saudi Arabia

BackgroundAntimicrobial resistance (AMR) and drug resistance have emerged as major global health concerns, threatening the effectiveness of antimicrobial agents and compromising patient outcomes [21]. The rapid spread of resistant pathogens poses significant challenges to healthcare systems worldwide, leading to increased morbidity, mortality, and healthcare costs [20]. Methods Search StrategyTo find pertinent studies released up until September 2023, a thorough search was done in electronic databases like PubMed, Embase, and Scopus. The search method combined terms linked to Saudi Arabia, drug resistance, and antimicrobial resistance (AMR). The specific search terms and Boolean operators used were tailored to the requirements and functionalities of each database. ResultsThe systematic review includes 25 papers in total, representing various Saudi Arabian healthcare environments and patient groups. The prevalence of AMR varied across different pathogens and antimicrobial agents. The most resistant Enterobacteriaceae were carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum -lactamase-producing Enterobacteriaceae (ESBL), and methicillin-resistant Staphylococcus aureus (MRSA). The full manuscript will report the pooled prevalence rates and 95% CIs for each resistance type. The rates for such bacteria were 38.7%, 26.4%, and 15.2% respectively suggesting an imminent need for improvement in surveillance measures & interventions to reduce the burden of AMR (Antimicrobial Resistance). ConclusionThe prevalence of antibiotic resistance (AMR) is alarmingly high in Saudi Arabia. The aim of this study was to examine the prevalence of AMR across different types of pathogens and antimicrobial agents. A meta-analysis was conducted to quantify the pooled prevalence of each type of resistance across hospitals, environments, and food samples from Saudi Arabian locations. The study identified three types of resistance: carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum -lactamaseproducing Enterobacilli (ESBL), and methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, the study identified several risk factors associated with AMR, including prior antibiotic use, healthcare-associated infections, and prolonged hospital stays.

Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-responsive Basal Ganglia Disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene

The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease’s rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. In this study, we have generated two clones of induced pluripotent stem cells (iPSCs) from a 10-year-old female BTBGD patient carrying a homozygous mutation for the pathogenic variant in exon 5 of the SLC19A3 gene, c.1264A > G (p.Thr422Ala). We have confirmed the pluripotency of the generated iPS lines and successfully differentiated them to neural progenitors. Because our understanding of genotype–phenotype correlations in BTBGD is limited, the establishment of BTBGD-iPSC lines with a homozygous SLC19A3 mutation provides a valuable cellular model to explore the molecular mechanisms underlying SLC19A3-associated cellular dysfunction. This model holds potential for advancing the development of novel therapeutic strategies.

Chronic mucocutaneous candidiasis due to signal transducer and activator of transcription 1 mutation in a Saudi patient: a case report

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency condition caused by a genetic abnormality that increases the risk of recurrent and persistent skin, nail and mucous membrane infections with Candida species, typically Candida albicans. Signal transducer and activator of transcription 1 (STAT 1) gene mutation is a genetic trigger that causes CMC, which increases the risk of infections, multisystem disorders and cancer susceptibility. We describe the first case of a Saudi female patient with clinical features of CMC with an underlying (STAT 1) gene mutation.

Accelerated Extensive Lung Fibrosis Post–COVID-19 Immunization in an Asthmatic Patient

We describe a unique case of a 60-year-old asthmatic Saudi patient who developed acute respiratory distress syndrome (ARDS) and accelerated lung fibrosis after the administration of the second dose of the COVID-19 mRNA vaccine. This patient presented to the emergency room with a four-day history of fever, shortness of breath, and cough. His hospitalization was complicated by non-ST segment elevation myocardial infarction, non-sustained ventricular tachycardia, and a lowered Glasgow Coma Scale. He was intubated at a P/F ratio of 73 mmHg and a peak inspiratory pressure of 46 cmH2O. His antibiotics had to be modified, as he had QT prolongation. Additional anti-pseudomonal, anti-anaerobe, and anti-fungal coverings were empirically given, which were later switched to colistin based on the results of a sputum culture. On ICU day 17, the patient went into cardiac arrest due to severe ARDS and septic shock. Despite attempts at resuscitation, he was unable to be revived.

Unique laparoscopic emergency management of traumatic obstructed abdominal wall hernia: A case report and review of literature

Abstract Traumatic abdominal wall hernia (TAWH) is a rare clinical occurrence, with only limited cases published since 1906. This type of hernia is primarily caused by low- or high-energy blunt force trauma, resulting in damage to abdominal wall musculature while the skin is intact. The diagnosis and management of TAWH poses a lot of challenges and complexities. Herein, we present a case of a 32-year-old male Saudi patient who sustained significant abdominal trauma as a driver involved in a front collision while wearing a seat belt. Upon arrival at the trauma center, the patient was hemodynamically stable and exhibited clinical signs of left flank bulge, seat belt sign, and abdominal bruising. First, a focused assessment with sonography for trauma (FAST) was performed, which revealed minimal free fluid in the abdomen. Subsequent contrast-enhanced IV computed tomography (CT) scan confirmed a 3.6-cm left lateral abdominal wall defect with herniation of short segments of the large and small bowel loops and adjacent subcutaneous fluid. Following initial observation, the patient developed signs of bowel obstruction. A repeat CT scan showed interval progression of the hernia, partial small bowel obstruction, and other concerning findings. An emergency laparoscopic exploration revealed a large defect at the left lumber region containing omentum and long segments of the small bowel with mild distension. The bowel and omentum were reduced. The surgical repair included herniorrhaphy and mesh placement. The patient recovered well and was discharged on the third postoperative day. This case underscores the importance of thorough evaluation and timely intervention in TAWHs. Rapid surgical management, aided by advanced imaging techniques, can lead to favorable outcomes even in complex cases involving bowel herniation and associated complications.

Generation of iPSC lines (KAIMRCi003A, KAIMRCi003B) from a Saudi patient with Dravet syndrome carrying homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A

The most prevalent form of epileptic encephalopathy is Dravet syndrome (DRVT), which is triggered by the pathogenic variant SCN1A in 80% of cases. iPSCs with different SCN1A mutations have been constructed by several groups to model DRVT syndrome. However, no studies involving DRVT-iPSCs with rare genetic variants have been conducted. Here, we established two DRVT-iPSC lines harboring a homozygous mutation in the CPLX1 gene and heterozygous mutation in SCN9A gene. Therefore, the derivation of these iPSC lines provides a unique cellular platform to dissect the molecular mechanisms underlying the cellular dysfunctions consequent to CPLX1 and SCN9A mutations.

Successful use of emapalumab in refractory hemophagocytic lymphohistiocytosis in a child with Chédiak–Higashi syndrome: a case report

BackgroundHemophagocytic lymphohistiocytosis is a life-threatening disease heralded by fever, cytopenia, hepatosplenomegaly, and multisystem organ failure. Its association with genetic mutations, infections, autoimmune disorders, and malignancies is widely reported.Case presentationA 3-year-old male Arab Saudi patient with insignificant past medical history and parental consanguinity presented with abdominal distension of moderate severity and persistent fever despite receiving antibiotics. This was accompanied by hepatosplenomegaly and silvery hair. The clinical and biochemical profiles were suggestive of Chédiak–Higashi syndrome with hemophagocytic lymphohistiocytosis. The patient received the hemophagocytic lymphohistiocytosis-2004 chemotherapy protocol and had multiple hospital admissions mainly due to infections and febrile neutropenia. After achieving the initial remission, the patient’s disease reactivated and did not respond to reinduction with the hemophagocytic lymphohistiocytosis-2004 protocol. Due to the disease reactivation and intolerance of conventional therapy, the patient commenced emapalumab. The patient was successfully salvaged and underwent an uneventful hematopoietic stem cell transplantation.ConclusionsNovel agents such as emapalumab can be helpful for the management of refractory, recurrent, or progressive disease, while avoiding the toxicities of conventional therapy. Due to a paucity of available data on emapalumab, additional data are needed to establish its role in hemophagocytic lymphohistiocytosis treatment.

CAD-CAM Designed Ceramic Veneer for the Restoration of Peg-shaped Lateral Incisor: Case Report

Peg shaped lateral incisors are considered to be the most common discrepancy concerning tooth size. This results in reduced size of the tooth, anterior diastema, and most often an unpresentable smile. Now a days, the concepts of Adhesive Dentistry and wider use of ceramic veneers have allowed all ceramic restorations to be more acceptable in terms of function and esthetics as well as establishing a good smile harmony. The aim of the clinical report presented, is to demonstrate a conservative approach of treatment so as to improve an esthetically disharmonious smile resulting from a unilateral peg-shaped lateral incisor. Here the authors present a case of 33 years old Saudi patient, who sought treatment for solving his esthetically disharmonious smile. Digital Impression guides were utilized for planning and fabricating Lithium Disilicate veneers. This was done to restore the size, morphology, function, as well as the esthetics of upper lateral incisors including the overall smile of the patient. The veneers using Lithium disilicate provided the harmonization of smile of the patient. It further resulted in recovering of the tooth size including its shape as well as anatomical characteristics.

Novel biallelic AHR splice site mutation cause isolated foveal hypoplasia in Saudi patient

AbstractPurpose: To study the clinical and molecular findings of a nonconsanguineous Saudi family with one affected 12 years boy affected by isolated foveal hypoplasia with no signs of infantile nystagmus.Methods: Comprehensive clinical and molecular approaches were applied including detailed ophthalmological examination followed by whole‐exome sequencing (WES).Results: Detailed ophthalmological examination revealed bilateral isolated foveal hypoplasia with the absence of the avascular zone. Novel homozygous aryl hydrocarbon receptor (AHR) splice site mutation; NM_001621.4: c.899_908 + 15del (p. ?) was identified and segregated within the family members.Conclusions: Our identified novel splice‐site AHR mutation supports the pathogenicity of the AHR gene and expands its phenotypic spectrum. Our study represents the first report of autosomal recessive isolated foveal hypoplasia without infantile nystagmus in the literature and the second reported AHR mutation with autosomal recessive isolated foveal hypoplasia post the original cloning paper.

Adult-Onset Hereditary Spastic Paraplegia 15 in a Saudi Patient with A Compound Heterozygous Variant in the ZFYVE26Gene.

Hereditary spastic paraplegia (HSP) 15 is an autosomal recessive neurodegenerative disease caused by homozygous or heterozygous point mutations in the ZFYVE26 gene that encodes the spastizin protein, located on chromosome 14q22-q24. Hereditary spastic paraplegia has been rarely reported in Saudi Arabia. In this article, we reported a rare case of adult-onset HSP 15 with a pure form of the disease in a Saudi patient with a compound heterozygous variant in the ZFYVE26 gene. The present case suggests that a compound heterozygous mutation in the ZFYVE26 may be associated with a later-onset disease and a milder phenotype. Given the low prevalence of the disease as well as heterogenicity and variability of its presenting symptoms, HSP 15 may be difficult to diagnose. However, early diagnosis is important to prevent unnecessary extensive investigations, facilitate early symptomatic management and provide genetic counseling for family planning to those affected and their first and second-degree relatives.

Scrotal Kaposi’s sarcoma in an immunocompetent patient: A case report and review of the literature

Kaposi’s sarcoma (KS) is a malignancy that generally affects the skin. It may be systemic with internal organ involvement, originating from the vascular endothelium. It is an acquired immunodeficiency syndrome (AIDS)-defining illness. Human herpes virus-8 (HHV-8) infection is involved in its pathogenesis. KS lesions have a general distribution, often involving the skin of the feet and legs and, to a lesser extent, the hands, arms, and trunk. Isolated scrotal involvement in an immunocompetent patient is a highly rare presentation. Herein, we present an immunocompetent Saudi patient with scrotal KS. A review of the related literature is also presented.

Clinical and diagnostic characteristics of complex III mitopathy due to novel BCS1L gene mutation in a Saudi patient

BackgroundOf the many types of mitochondrial diseases, mutations affecting BCS1L gene are regarded as chief cause of the defective mitochondrial complex-III, affecting normal mitochondrial functioning, and leading to wide variety of phenotypes.Case presentationIn this case report we describe a novel genotype linked to a unique phenotype in a Saudi patient born of a consanguineous marriage. Detailed genetic analysis and whole genome sequencing identified a novel homozygous missense mutation in exon 5 c.712A > G (p.Ser328Gly) of the BCS1L gene, with predicted deleterious effects on the functioning AAA+-ATPase domain of the protein characterized by distinct clinical presentation associated with profound multisystem involvement, conductive hearing loss, absent external auditory canal, low posterior hair line, short neck, micro and retrognathia, over riding fingers, rocker bottom foot, small phallus with bilateral absent testis (empty scrotum) and intolerable lactic acidosis.ConclusionsA pathogenic effect of this novel BCS1L mutation was reflected in the patient with his failure to thrive and a complex clinical and metabolic phenotype.

Assessment of the Quality of Saudi Patient Information Leaflets (PILs) Based on the Accuracy of Physical Description and Frequency of Solid Dosage Forms.

The physical description of dosage forms is one of the most important considerations in avoiding patient confusion and minimizing medication errors. This study aimed to determine the quality and accuracy of the physical descriptions in patient information leaflets (PILs). This cross-sectional study constituted a total of 200 drugs and PILs that were randomly selected, by pharmacy students, from Al-Dawaa community pharmacies in the Hail region of Saudi Arabia, from January 2021 to July 2021. The drugs and PILs were thoroughly evaluated in accordance with the Gulf Cooperation Council (GCC) guidelines for PILs. The accuracy screening of the total solid dosage forms (capsules + tablets) revealed that 45% showed complete accuracy and compliance, 1.5% showed poor accuracy and compliance, and 53% showed no accuracy and no compliance with the GCC guidelines and the Saudi Food and Drug Authority (SFDA) guidelines. In the frequency test, color, shape, and imprints accounted for 95.6%, 79.1%, and 73.6%, respectively. However, the size of the dosage form was the least (2.2%) used physical description feature. These findings recommend pharmaceutical companies to pay more attention to the written physical description in their PILs. Additionally, the process of PIL approval should be optimized, evaluated, and updated systematically to ensure that they contain the essential information.

Pathogenic germline mutations prevalence in Saudi patients with pancreatic ductal adenocarcinoma.

538 Background: While the majority of pancreatic ductal adenocarcinoma(PDAC) cases are sporadic, about 10% related to familial and hereditary component. Multiple studies have shown that germline genetic testing regardless of family history for patients with PDCA is feasible and more likely to identify the carrier of pathogenic mutations. There is no data about the prevalence of pathogenic germline mutations in Saudi population. We aimed to study the prevalence of these mutations in Saudi patient patients with PDAC regardless of the family history of cancer. Methods: By using our cancer genetics database, we analyzed all the confirmed cases of PDAC who were referred to the cancer genetic clinic at King Abdulaziz medical city in Riyadh, Kingdom of Saudi Arabia. Since November 2018, a comprehensive hereditary cancer gene panel (including 70 genes) is offered to all referred PDAC cases regardless of their family history of cancer after obtaining a genetic counselling assessment and an informed consent. Results: Between November 2018 and August 2021, a total of 88 patients with PDAC cases have been tested. The median age was 60 and the majority of patients were males (n=56, 64%). Most of the patients had stage IV disease (n=75, 85.23%). The genetic result was available for 86 patients. Pathogenic variant(PVs) was reported in 8.1% (n=7), variant of uncertain significance (VUSs) was reported in 15% (n=13) while no mutation reported in the rest of the patients. The PVs reported were BRCA2 (n=4), BRIP1 (n=1), PMS1(n=1) and MRE11 (n=1). All the carriers of the PVs had no documented family history of breast, ovarian or pancreatic cancers at the time of genetic counselling. Conclusions: This study confirms the importance of genetic testing in all patients with PDAC regardless of the family history. This is in line with previous studies from other populations. This is the first study from Saudi patients with PDAC and to the best of our knowledge, the first study in Arab population.

The Impact of COVID-19 Pandemic on the Increased Number of Deaths Due to Heart Attack and Stroke Among Saudis And Egyptians: A Comparative Study

Background: Many articles describing the comorbidities on the gastrointestinal, neurological, and respiratory manifestations of the COVID-19 infection. The cardiovascular system is often affected and caused acute myocardial infarction, venous thromboembolic events, and monitoring with high sensitivity cardiac troponin. Ischemic stroke remains the most common subset of neurological manifestations in COVID- 19 infection. Aim of research: This comparative cross-sectional retrospective study was carried out to assess and compare the association between COVID -19 infection and the risk of acute ischemic stroke among both Saudi and Egyptian infected patient. Subjects and Methods: Data was collected through a well-structured questionnaire, distributed among patients who infected with COVID-19 in Saudi Arabia and Egypt. The questionnaire includes patients’ Socio-demographic and history of chronic diseases, laboratory investigations, time of getting stroke after COVID-19 infection and symptoms of COVID infection and stroke, as well as stroke outcomes. Then, data was statistically been analyzed using (SPSS, version 25) statistical program. Results: 635 participants (288 Egyptians and 347 Saudis) were included in this study who were infected with COVID-19 and completed the data of the questionnaire. Most of participants were young (< 46 years old), and females. The total percent of participants who had stroke due to infection with COVID-19 and recovered without side effect was 1% & 1.2%, while 1.7% & 0.9% recovered but having some side effects among Egyptians and Saudis respectively. All these patients with stroke had medical history of cardiovascular diseases, hypertension, diabetes, dyslipidemia with elevated levels of D-dimer, C-reactive protein, white blood cell, neutrophils and low level of lymphocytes. conclusion: Our research supports the fact that COVID- 19 infection is associated with a clinical outcome of ischemic stroke that tend to the highest rate of mortality. Also, more research is needed to examine the neurological implications of COVID-19 disease.

Chronic progressive external ophthalmoplegia in a Saudi patient with a mutation in the POLG gene successfully managed with bilateral frontalis sling

Hussein Algahtani, Bader Shirah, Khalid Alsaggaf, Mohammad H. Al-Qahtani, Angham Abdulrahman Abdulkareem, Muhammad Imran Naseer, and Ahmad R. Abuzinadah. J Genet Med 2021;18:121-6. https://doi.org/10.5734/JGM.2021.18.2.121

HIV-2 Vpx neutralizes host restriction factor SAMHD1 to promote viral pathogenesis

SAMHD1, a human host factor found in myeloid cells which restricts HIV-1 replication. It depletes the dNTPs pool for viral cDNA syntheses, thus preventing the viral replication in the cells. The viral accessory protein, Vpx, exists only in SIVmac/HIV-2 particles. Vpx in SIVmac can induce proteosomal degradation of SAMHD1, which then leads to a decrease in the cytoplasmic dNTP pool. The protein–protein interaction between Vpx and SAMHD1 and its consequences are still unclear. Methods: In this study, we cloned, for the first time, Vpx gene from a HIV-2 infected patient and found up to 30% sequence variation compared to known HIV-2 strains. We then analyzed the role of SAMHD1 protein expression in transfected THP-1 and U937 cells by transfecting with the Vpx gene derived from SIVmac, HIV-2 from the NIH sample as well as HIV-2 from a Saudi patient. We found that Vpx gene expression led to reduced levels of intracellular SAMHD1. When the supernatants of the transfected cell lines were examined for secreted cytokines, chemokines and growth factors, Vpx expression seemed to be suppressive of pro-inflammatory response, and skewed the immune response towards an anti-inflammatory response. These results suggest that Vpx can act at two levels: clearance of intracellular restriction factor and suppression of cytokine storm: both aimed at long-term latency and host–pathogen stand-off, suggesting that Vpx is likely to be a potential therapeutic target.

A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families.

Half of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.