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 Table of Contents  
Year : 2022  |  Volume : 22  |  Issue : 4  |  Page : 232-235

An epiphanic case of X-linked Alport syndrome caused by a hitherto unreported COL4A5 gene mutation

1 Department of Medicine, The University of Toronto, Toronto, Canada
2 Department of Nephrology, NU Hospitals, Bengaluru, Karnataka, India
3 Dhitiomics Technologies Pvt Ltd, Bengaluru, Karnataka, India
4 Department of Medicine,Cleveland Clinic Foundation/Fairview Hospital, Connecticut, United States

Date of Submission14-Dec-2021
Date of Acceptance03-Mar-2022
Date of Web Publication22-Sep-2022

Correspondence Address:
Dr. Avinash Rao Ullur
Clinical Fellow in Adult Nephrology, Department of Medicine, The University of Toronto, Toronto
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jesnt.jesnt_42_21

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Alport Syndrome (AS) is an inherited glomerular disease, which invariably progresses to End Stage Kidney Disease (ESRD). It can be associated with hearing impairment and ocular defects. The disease can be X-linked caused by mutations in the Type 4 Collagen alpha 5 chain (COL4A5), Autosomal Recessive (ARAS) or Autosomal Dominant (ADAS) caused by mutations in the Type 4 Collagen alpha 3 chain (COL4A3) or alpha 4 chain (COL4A4). We report a novel mutation in COL4A5 Gene causing XLAS resulting in Chronic Kidney Disease in a 34-year-old male. Whole genome sequencing of the patient, showed hemizygous variant (c.1690G>C, p. Gly564Arg) in the COL4A5 gene. The same variant was detected in his mother and his only daughter establishing that the mutation is pathogenic.

Keywords: Alport syndrome, COL4A5, ESRD, genetics, mutation

How to cite this article:
Ullur AR, Subramanian P, SantanaRaman R, Rangarajan D, Gunasekaran D, Rao SN. An epiphanic case of X-linked Alport syndrome caused by a hitherto unreported COL4A5 gene mutation. J Egypt Soc Nephrol Transplant 2022;22:232-5

How to cite this URL:
Ullur AR, Subramanian P, SantanaRaman R, Rangarajan D, Gunasekaran D, Rao SN. An epiphanic case of X-linked Alport syndrome caused by a hitherto unreported COL4A5 gene mutation. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Jun 8];22:232-5. Available from: http://www.jesnt.eg.net/text.asp?2022/22/4/232/356690

  Introduction Top

Alport syndrome is an inherited glomerular disease with progressive loss of renal function along with association of eye abnormalities and hearing loss. Collagen type IV alpha 5 chain (COL4A5) gene has 250 kb of genomic DNA with 51 exons encoding a 6.5-kb transcript. The alpha 5 chain contains 1685 amino acids [1]. The first COL4A5 mutations were described by Barker et al. [2]. There are several known mutations associated with this syndrome, with newer variants being detected now and then. Alport syndrome is a heterogeneous disease, and numerous phenotypes have been described based on the rate of progression to end-stage kidney disease (ESKD), presence or absence of deafness, and other extrarenal manifestation like ocular changes, macrothrombocytopenia, and diffuse esophageal leiomyomatosis [3]. The common COL4A5 mutations are deletions, insertions, missense mutations, nonsense mutations, and splice-site mutations. A ‘European Community Alport Syndrome Concerted Action’ has been established to determine the genotype–phenotype correlations. Large deletions, nonsense mutations, or small mutations changing the reading frame result in a 90% probability of developing ESKD before 30 years of age. The risk is reduced to 50–70% if the mutations were missense or slice-site [4]. It is interesting to note the variations in the presentation of the syndrome and to determine the outcomes which help in planning the management in these cases. It is unusual to find out of the box genetic changes in everyday life and if found, they need to be reported so as to help the treating physician in being aware of such conditions and their prognosis.

  Case report Top

A 34-year-old gentleman presented to us in November 2014 with renal dysfunction (serum creatinine 2.63 mg/dl) and hypertension detected while being evaluated for blurred vision. There was no prior history of recurrent headache, visual disturbances, and loss of consciousness or seizures. There was no history of claudication pain in the limbs, excess sweating, palpitations, or weakness in the limbs. Patient did not have nocturia, hematuria, or frothy urine. There was no history of skin rashes, joint pain, myalgia, easy fatigability, oral ulcers, or alopecia. Patient denied history of decreased hearing. Patient had no past ailments including diabetes, tuberculosis, or recurrent childhood infections. There was no family history of similar illness.

On evaluation, he was detected to have proteinuria with a urine protein creatinine ratio of 6.37. There were five red blood cells/HPF noted in the urine examination. He had deranged renal function with serum creatinine of 2.63 mg/dl ([Table 1]). His complete hemogram was normal. He had metabolic acidosis with serum bicarbonate level of 18.5 mEq/l and serum potassium was 5 mEq/l. He had hypoalbuminemia (serum albumin – 3.2 mg/dl) and hyperuricemia with a serum uric acid of 7.5 mg/dl. Thyroid profile showed evidence of hypothyroidism (thyroid-stimulating hormone – 12.46 IU/ml). Rest of the electrolytes, metabolic parameters, and liver function tests were normal. He had negative serology for the presence of HIV, hepatitis B, and hepatitis C. Ultrasonography of the abdomen and pelvis showed bilateral smallish kidneys with increased cortical echo texture and reduced cortico-medullary differentiation. Echocardiography showed evidence of borderline concentric left ventricular hypertrophy and grade 1 diastolic dysfunction. In view of history of blurred vision, he underwent ophthalmic examination, which revealed resolving retinal edema and mild anterior lenticonus. Suspecting Alport syndrome, a pure-tone audiometry test was done, which detected presence of bilateral moderate sloping sensorineural hearing loss. A genetic analysis was requested in view of strong evidence toward presence of Alport syndrome, and the report revealed the presence of XL inheritance, COL4A5 gene mutation, and NM_033380.2 transcript confirmed by targeted Sanger sequencing of the region. CDS position, variation, and zygosity were c.1690>C and hemizygous, respectively. The amino acid change noted was Gly564Arg and the predicted effect was deleterious. This was a missense mutation. His 61 years old mother did not have eye manifestations of Alport syndrome and her pure-tone audiomety result was normal. Her urine analysis and renal function tests were normal. She underwent genetic analysis, which revealed similar mutation as that of the patient and was reported to be a carrier. His daughter, 5 years old, who was asymptomatic with normal urinalysis and renal functions, also had the same mutation and was reported to be a carrier. This variant had not been reported earlier. This was registered with National Center for Biotechnology Information. ClinVar; [VCV000242342.1], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000242342.1 (accessed May 8, 2021). He was on regular outpatient follow-up for his chronic kidney disease. He was vaccinated for hepatitis B, Pneumococcus, and influenza. His renal function gradually deteriorated over years ([Fig. 1]). In June 2019, 5 years after the initial diagnosis, he presented with uremic symptoms. He was initiated on hemodialysis through right internal jugular double-lumen nontunneled catheter as his arteriovenous fistula was yet to mature. He is presently on thrice weekly maintenance hemodialysis and is doing well. He has been registered for deceased donor kidney transplantation.
Table 1: Blood and urine analysis reports of the patient at follow-ups

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Figure 1: eGFR (ml/min/1.73m2) decline in the succeeding years after Alport syndrome diagnosis in the patient. eGFR, estimated glomerular filtration rate.

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  Discussion Top

The incidence of Alport syndrome ranges from 1/5000 to 1/50 000 among differrent populations [5]. Alport syndrome is a disease affecting the basement membrane and could be owing to the mutation of several genes encoding members of collagen 4 protein family [6]. A recent classification of Alport syndrome has described four different modes of genetic transmission, which include (a) X linked (majority of cases), (b) autosomal dominant (5% of cases), (c) autosomal recessive (10–15% of cases), and (d) digenic (rare) [7]. In X-linked disease, males are mostly affected, and there is no father-to-son transmission. The females, although are typically heterozygotes for disease causing variants, almost always have some degree of hematuria and rarely develop chronic kidney disease owing to ‘ Lyonization More Details’ or random inactivation of one of the X chromosomes [8]. In the autosomal recessive variant, females are affected as severely as males, and severity is almost identical with X-linked disease in males [9]. In the autosomal dominant inheritance and the rare digenic variants, the presentation could be variable ranging from microscopic hematuria to frank kidney failure [10,11]. X-linked Alport syndrome is a progressive disease, wherein the affected males will reach end-stage renal failure in the early or mid-adulthood. The earliest presentation of X-linked disease is usually an asymptomatic microscopic hematuria. Gross hematuria would occur if associated with upper respiratory tract infection [12]. If hematuria is absent by age of 10 years, renal dysfunction is unlikely to occur [13]. Over years, patients develop progressive renal disease and reach end-stage renal failure by 16–35 years in X-linked Alport syndrome [14]. With respect to other associated manifestations, a familial study has reported that 85% of the boys and 15% of the girls with X-linked Alport syndrome have audiologically detectable sensorineural hearing loss by the age of 15 years [2]. Approximately 20–30% of the males with X-linked Alport syndrome have anterior lenticonus with associated retinal changes [15]. Leiomyomas are detectable in 2–5% of the patients who have 5’ end microdeletion of COL4A5, which may extend to COL4A6 gene [16,17]. Aortic aneurysm are relatively rare presentation in young individuals [18,19]. In the presented case, the patient had presented to us with chronic kidney disease stage 4, which progressed to end-stage renal disease (ESRD) in the following 5 years. Although it is premature to comment, it was observed that the progression of the disease in this case is slower as compared with other established variants. There was only a minimal eye change in this case with bilateral sensorineural hearing loss. The female carriers did not have eye or ear abnormalities.

In a study by Zhang et al. [20], which included 87 males with X-linked Alport syndrome, the degree of symmetrical sensorineural loss had a significant correlation with genotype, renal function, and age. Similarly, a large familial study by Jais et al. [4] also established a strong phenotype–genotype correlation in X-linked Alport syndrome-affected males. Żurowska et al. [21] has described a cohort of mild XLAS owing to COL4A5 G624D variant in predominantly Slavic ethnicity, where the males developed late-onset ESRD. The males have a 50% cumulative probability of reaching ESRD by the age of 54 years. Our patient reached ESRD at the age of 39 years, which is in agreement with the ‘European Community Alport Syndrome Concerted Action’ wherein the probability of developing ESRD before the age of 30 years decreases from 90 to 50% with missense mutations in the COL4A5 gene [4]. On the contrary, there is no established genotype–phenotype correlation among female carriers [22]. In the present case, the genotype–phenotype correlation can be established only after few more cases of this particular variant are reported and their natural history is studied. In India, it is worthwhile to consider starting a registry for Alport syndrome cases, which would help in studying the disease systematically in the future.

  Conclusion Top

Alport syndrome is clinically heterogeneous. There exists a considerable allelic heterogeneity. We now know that patients with Alport syndrome can reach ESKD from as early as teen age to as late as 50 years of age. Newer mutations in the human type 4 collagen gene are being reported. Understanding the natural course of the disease caused by these mutations would help the treating physicians to better evaluate and manage these patients. Our patient had a novel COL4A5 mutation, which probably is less severe compared with the other mutations because he reached ESKD at the age of 39 years. However, the exact genotype–phenotype correlation can be established only after a few more cases of this particular variant are reported and studied.

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Conflicts of interest

Authors do not have any conflict of interest.

  References Top

Zhou J, Hertz JM, Leinonen A, Tryggvason K Complete amino acid sequence of the human a5IV) collagen chain and identification of a single-base mutation in exon 23 converting glycine 521 in the collagenous domainto cysteineinan Alport syndrome patient. J Biol Chem 1992; 267:12475–12481.  Back to cited text no. 1
Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, et al. Identification of mutations in the COL4A5 collagen genes Alport syndrome. Science 1990; 248:1224–1227.  Back to cited text no. 2
Feingold J, Bois E, Chompret A, Broyer M, Gubler MC, Grünfeld JP Genetic heterogeneity of Alport syndrome. Kidney Int 1985; 27:672–677.  Back to cited text no. 3
Jais JP, Knebelmann B, Giatras A, De Marchi M, Rizzoni G, Renieri A, et al. X-linked Alport Syndrome. Natural History in 195 families and genotype-phenotype correlations in males. JASN 2000; 11:649–657.  Back to cited text no. 4
Kashtan CE Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 1998; 9:1736.  Back to cited text no. 5
Kashtan CE, Ding J, Garosi G, Heidet L, Masella L, Nakanishi K, et al. Alport syndrome: a unified classification of genetic disorders of collagen IVα345: a position paper of the Alport Syndrome Classification Working Group. Kidney Int 2018; 93:1045.  Back to cited text no. 6
Nozu K, Nakanishi K, Abe Y, Udagawa T, Okada S, Okamoto T, et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin Exp Nephrol 2019; 23:158–168.  Back to cited text no. 7
Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F Alport syndrome in women and girls. Clin J Am Soc Nephrol 2016; 11:1713–1720.  Back to cited text no. 8
Dagher H, Buzza M, Colville D, Jones C, Powell H, Fassett R, et al. A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport’s syndrome. Am J Kidney Dis 2001; 38:1217–1228.  Back to cited text no. 9
Furlano M, Martínez V, Pybus M, Arce Y, Crespí J, Venegas MDP, et al. Clinical and genetic features of autosomal dominant alport syndrome: a cohort study. Am J Kidney Dis 2021; 78:560.  Back to cited text no. 10
Mencarelli MA, Heidet L, Storey H, van Geel M, Knebelmann B, Fallerini C, et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet 2015; 52:163.  Back to cited text no. 11
Gubler M, Levy M, Broyer M, Naizot C, Ganzales G, Perrin D, Habib R Alport’s syndrome. A report of 58 cases and a review of the literature. Am J Med 1981; 70:493.  Back to cited text no. 12
Kashtan CE Alport syndrome. An inherited disorder of renal, ocular and cochlear basement membranes. Medicine Baltimore 1999; 78:338.  Back to cited text no. 13
Gubler MC Inherited diseases of the glomerular basement membrane. Nat Clin Pract Nephrol 2008; 4:24.  Back to cited text no. 14
Byrne MC, Budisavjevic MN, Fan Z, Self SE, Ploth DW Renal transplant in patients with Al-port’s syndrome. Am J Kidney Dis 2002; 39:769.  Back to cited text no. 15
Dahan K, Heidet L, Zhou J, Mattler G, Leppig KA, Proesmans W, et al. Smooth muscle tumors associated with X-linked Alport syndrome: carrier deletion in females. Kidney Int 1995; 48:1900.  Back to cited text no. 16
Uliana V, Marcocci E, Mucciolo M, Meloni I, Izzi C, Manno C, et al. Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2. Peditr Nephrol 2011; 25:717.  Back to cited text no. 17
Voices C, hunt CD, Heary RF Ruptured intracranial aneurysm in adolescent with Alpert’s syndrome – a new expression of type IV collagenopathy – a case report. Surg Neurol 2000; 54:68.  Back to cited text no. 18
Lyons OT, St Johan ER, Morales JP, Chan YC, Taylor PR Ruptured thoracoabdominal aortic aneurysm in a renal transplant patient with Alpert’s syndrome. Ann Vasc Sure 2007; 21:816.  Back to cited text no. 19
Zhang X, Zhang Y, Zhang Y, Gu H, Chen Z, Ren L, et al. X-linked Alport syndrome: pathogenic varient features and further auditory genotype-phenotype correlations in males. Orphaned J Rare Dis 2018; 13:229.  Back to cited text no. 20
Żurowska AM, Bielska O, Daca-Roszak P, Jankowski M, Szczepańska M, Roszkowska-Bjanid D, et al. Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife. Kidney Int 2021; 99:1451–1458.  Back to cited text no. 21
Yamamura T, Nozu K, Fu XJ, Nozu Y, Ye MJ, Shono A, et al. Natural his- tory and genotype-phenotype correlation in female X-linked Alport syndrome. Kidney Int Rep 2017; 2:850-.  Back to cited text no. 22


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