Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study

Furlano, Mónica; Martínez, Víctor; Pybus, Marc; Arce, Yolanda; Crespí, Jaume; Venegas, María del Prado; Bullich, Gemma; Domingo, Andrea; Ayasreh, Nadia; Benito, Silvia; Lorente, Laura; Ruíz, Patricia; González, Vanesa López; Arlandis, Rosa; Cabello, Elisa; Guirado, Lluís; Ars, Elisabet; Torrá, Roser

doi:10.1053/j.ajkd.2021.02.326

Cited by 62 publications

(85 citation statements)

References 46 publications

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“…The genetics of Alport syndrome are complex with several modes of inheritance: semidominant X-linked Alport syndrome (XLAS, MIM# 301050) for COL4A5 as well as autosomal recessive (ARAS, MIM# 203780) and dominant (ADAS) for both COL4A3 (MIM# 104200) and COL4A4. Finally, digenic inheritance with variants in different COL4A3-5 genes has been described (Furlano et al 2021). XLAS is probably the most prevalent cause of kidney failure among Alport subtypes and males with XLAS or biallelic individuals with ARAS usually exhibit more severe disease while heterozygous females with pathogenic COL4A5 variants are generally more mildly affected (Savige et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…XLAS is probably the most prevalent cause of kidney failure among Alport subtypes and males with XLAS or biallelic individuals with ARAS usually exhibit more severe disease while heterozygous females with pathogenic COL4A5 variants are generally more mildly affected (Savige et al 2016). Monallelic pathogenic COL4A3/COL4A4 variants lead to a wide spectrum of manifestations, ranging from completely asymptomatic, or isolated haematuria to progressive CKD with extrarenal manifestations, variously referred to as autosomal dominant thin basement membrane nephropathy or ADAS (Furlano et al 2021;Gale 2013;van der Loop et al 2000). The reasons for this phenotypic spectrum is unclear but modifying genetic or environmental factors have been proposed (Furlano et al 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Monallelic pathogenic COL4A3/COL4A4 variants lead to a wide spectrum of manifestations, ranging from completely asymptomatic, or isolated haematuria to progressive CKD with extrarenal manifestations, variously referred to as autosomal dominant thin basement membrane nephropathy or ADAS (Furlano et al 2021;Gale 2013;van der Loop et al 2000). The reasons for this phenotypic spectrum is unclear but modifying genetic or environmental factors have been proposed (Furlano et al 2021). Pogression to kidney failure is less likely (and occurs later) than in XLAS or ARAS (Furlano et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

Mohamed

Tellez

Bergmann

et al. 2021

Annals of Human Genetics

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Alport syndrome is a genetic disorder affecting the basement membranes of the kidney, ear and eye, and represents a leading cause of monogenic kidney disease. Alport syndrome is genetically heterogeneous with three key genes involved (COL4A3-5) and several transmission patterns, including monogenic Xlinked, autosomal recessive/dominant and digenic. We report a consanguineous family where 13 individuals presented variable features of Alport syndrome including kidney failure on two generations and male-to-male transmission, suggesting autosomal dominant inheritance. COL4A3-5 gene panel analysis surprisingly reveals two distinct, confirmed splice-altering variants in COL4A3 (NM_000091.4: c.1150+5G>A and c.4028-3C>T) present in homozygous or compound heterozygous state in individuals with kidney failure. This adds a further mode of transmission for Alport syndrome where, in a consanguineous family, the independent segregation of two variants at the same locus may create a pseudodominant transmission pattern. These findings highlight the importance of a molecular diagnosis in Alport syndrome for genetic risk counselling, given the variable modes of inheritance, but also the pitfalls of assuming identity by descent in consanguineous families.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

Mohamed

Tellez

Bergmann

et al. 2021

Annals of Human Genetics

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“…The inheritance of COL4A3 and COL4A4 double heterozygous variants is complex, because the variants may be inherited on the same chromosome (in cis ) where inheritance is AD, or on different chromosomes (in trans ) where inheritance is AR [ 5 , 6 ]. The renal outcome appears to be worse with a combination of heterozygous COL4A3 and COL4A4 variants than with a single variant; however, further studies are needed [ 10 ]. Recent advice is that these individuals should also be treated with RAAS blockade if they have albuminuria or additional risk factors for progressive kidney disease such as hypertension [ 26 ], and other first-degree family members should be offered cascade genetics testing.…”

Section: Genotype-phenotype Correlation From Monogenic To Digenic Formsmentioning

confidence: 99%

The 2019 and 2021 International Workshops on Alport Syndrome

et al. 2022

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In 1927 Arthur Cecil Alport, a South African physician, described a British family with an inherited form of kidney disease that affected males more severely than females and was sometimes associated with hearing loss. In 1961, the eponymous name Alport syndrome was adopted. In the late twentieth century three genes responsible for the disease were discovered: COL4A3 , COL4A4 , and COL4A5 encoding for the α3, α4, α5 polypeptide chains of type IV collagen, respectively. These chains assemble to form heterotrimers of type IV collagen in the glomerular basement membrane. Scientists, clinicians, patient representatives and their families, and pharma companies attended the 2019 International Workshop on Alport Syndrome, held in Siena, Italy, from October 22 to 26, and the 2021 online Workshop from November 30 to December 4. The main topics included: disease re-naming, acknowledging the need to identify an appropriate term able to reflect considerable clinical variability; a strategy for increasing the molecular diagnostic rate; genotype-phenotype correlation from monogenic to digenic forms; new therapeutics and new therapeutic approaches; and gene therapy using gene editing. The exceptional collaborative climate that was established in the magical medieval setting of Siena continued in the online workshop of 2021. Conditions were established for collaborations between leading experts in the sector, including patients and drug companies, with the aim of identifying a cure for Alport syndrome.

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“…Most patients develop a mild phenotype but some of them (29%) progress and can reach ESRD later in life [ 22 , 23 ]. Extrarenal manifestations are unusual [ 24 ]. The variability can be so wide that even members of the same family, with the same variant, can express the disease differently [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

Martínez-Pulleiro

García-Murias

Fidalgo-Díaz

et al. 2021

IJMS

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Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

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Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study

Cited by 62 publications

References 46 publications

Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

Pseudodominant Alport syndrome caused by pathogenic homozygous and compound heterozygous COL4A3 splicing variants

The 2019 and 2021 International Workshops on Alport Syndrome

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

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