Rare Genetic Cause Research Articles

Progress in pediatric obesity: new and advanced therapies

In this review, we discuss new medical and surgical options for the treatment of children and adolescents with obesity. We review the impact of COVID-19 on this vulnerable population. We also discuss the recent availability of screening tests for rare genetic causes of obesity. COVID-19 increased the prevalence of obesity among children and adolescents. This population is at increased risk for severe disease. The field of pediatric obesity has benefited from the approval of two new antiobesity medications: liraglutide and setmelanotide. We discuss indications for their use. New guidelines for surgical options for the treatment of children and adolescents with obesity are reviewed. These options are increasingly used as part of the comprehensive care for these children. The epidemic of childhood obesity continues. COVID-19 and the associated isolation contributed to the problem. However, promising new medical and surgical therapies and screening tests for rare genetic causes of obesity are available. These new diagnostic and therapeutic options bring renewed enthusiasm to the treatment of children and adolescents with obesity and increased recognition that obesity is a chronic disease starting in childhood deserving intervention to prevent consequences.

Recurrent hemolytic uremic syndrome caused by DGKE gene mutation: a case report

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury without any association with preceding diarrhea. Dysregulation of the complement system is the most common cause of aHUS, and monoclonal humanized anti-C5 antibodies are now recommended as the first-line treatment for aHUS. However, if the complement pathway is not the cause of aHUS, C5 inhibitors are ineffective. In this study, we report the second reported case of aHUS caused by DGKE mutations in Republic of Korea. The patient was an 11-month-old infant who presented with prodromal diarrhea similar to typical HUS, self-remitted with conservative management unlike complement-mediated aHUS but recurred with fever. While infantile aHUS often implies genetic dysregulation of the complement system, other rare genetic causes, such as DGKE mutation, need to be considered before deciding long-term treatment with C5 inhibitors.

Testing for rare genetic causes of obesity: findings and experiences from a pediatric weight management program.

BackgroundGenetic screening for youth with obesity in the absence of syndromic findings has not been part of obesity management. For children with early onset obesity, genetic screening is recommended for those having clinical features of genetic obesity syndromes (including hyperphagia).ObjectivesThe overarching goal of this work is to report the findings and experiences from one pediatric weight management program that implemented targeted sequencing analysis for genes known to cause rare genetic disorders of obesity.Subjects/MethodsThis exploratory study evaluated youth tested over an 18-month period using a panel of 40-genes in the melanocortin 4 receptor pathway. Medical records were reviewed for demographic and visit information, including body mass index (BMI) percent of 95th percentile (%BMIp95) and two eating behaviors.ResultsOf 117 subjects: 51.3% were male; 53.8% Hispanic; mean age 10.2 years (SD 3.8); mean %BMIp95 157% (SD 29%). Most subjects were self- or caregiver-reported to have overeating to excess or binge eating (80.3%) and sneaking food or eating in secret (59.0%). Among analyzed genes, 72 subjects (61.5%) had at least one variant reported; 50 (42.7%) had a single variant reported; 22 (18.8%) had 2–4 variants reported; most variants were rare (<0.05% minor allele frequency [MAF]), and of uncertain significance; all variants were heterozygous. Nine subjects (7.7%) had a variant reported as PSCK1 “risk” or MC4R “likely pathogenic”; 39 (33.3%) had a Bardet-Biedl Syndrome (BBS) gene variant (4 with “pathogenic” or “likely pathogenic” variants). Therefore, 9 youth (7.7%) had gene variants previously identified as increasing risk for obesity and 4 youth (3.4%) had BBS carrier status.ConclusionsPanel testing identified rare variants of uncertain significance in most youth tested, and infrequently identified variants previously reported to increase the risk for obesity. Further research in larger cohorts is needed to understand how genetic variants influence the expression of non-syndromic obesity.

Distinct Autism Spectrum Disorder Phenotype and Hand-Flapping Stereotypes: Two Siblings with Novel Homozygous Mutation in TRAPPC9 Gene and Literature Review

Objective: Pathogenic mutations of the TRAPPC9 gene are the rare genetic causes of autosomal recessive intellectual disability (ID). There are several features that are not fully penetrant such as microcephaly, dysmorphic facial features, obesity, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and brain abnormalities in TRAPPC9 mutations. Methods: We performed whole-exome sequencing to evaluate 2 Turkish siblings with ASD and ID born to healthy and consanguineous parents. Parental samples were also analyzed, specifically targeting variants detected in these patients. Results: We present a novel homozygous mutation in the TRAPPC9 gene, c.484G>T (p.Glu162Ter). Additionally, we aim to provide a more comprehensive understanding of the clinical features of a novel homozygous TRAPPC9 mutation. In addition to ID, the siblings in this report suffered from ASD and specific stereotypes as hand-flapping behavior. Conclusion: Although there are inconsistencies in the presentation of ASD in TRAPPC9 mutations, repetitive behaviors (hand-flapping ) were typical in our cases and several previous reports. The current mutation was described to cause a homozygous premature termination codon that resulted in the absence of the TRAPPC9 protein. We suggest that TRAPPC9 mutations are not only related to ID but also to ASD and hand-flapping behaviors.

EP123: Design of a phase 2, double-blind, placebo-controlled trial of setmelanotide in patients with genetic variants in the melanocortin-4 receptor pathway

Rare genetic causes of obesity include variants in genes within the melanocortin-4 receptor (MC4R) pathway, a principal regulator of energy balance. Weight and hunger reductions following treatment with the MC4R agonist setmelanotide have been demonstrated in patients with obesity due to variants in multiple genes, including POMC, LEPR, SRC1, and SH2B1. We describe the design of DAYBREAK, a Phase 2 trial of setmelanotide in patients with additional specific gene variants based on an evidence-based framework that suggested relevance to the MC4R pathway (ClinicalTrials.gov identifier: NCT04963231).

Rare genetic causes of meningitis and encephalitis.

Differential diagnosis of meningitis and encephalitis is often very challenging because it cannot be determined based on symptoms, and the diseases have various causes. This article explains rare genetic causes of meningitis and encephalitis. Autoinflammatory disorders include cryopyrin-associated periodic syndromes, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. Furthermore, other genetic disorders, such as complement factor I deficiency, phosphatidylinositol glycan anchor biosynthesis class T mutation, and neuronal intranuclear inclusion disease, can present as meningitis and encephalitis.

Role of histidine decarboxylase gene in the pathogenesis of Tourette syndrome.

Tourette syndrome (TS) is caused by complex genetic and environmental factors and is characterized by tics. Histidine decarboxylase (HDC) mutation is a rare genetic cause with high penetrance in patients with TS. HDC‐knockout (KO) mice have similar behavioral and neurochemical abnormalities as patients with TS. Therefore, HDC‐KO mice are considered a valuable TS pathophysiological model as it reveals the underlying pathological mechanisms that cannot be obtained from patients with TS, thus advancing the development of treatment strategies for TS and other tic disorders. This review summarizes some of the recent research hotspots and progress in HDC‐KO mice, aiming to deepen our understanding of brain mechanisms relevant to TS. Furthermore, we encapsulate the possible brain nerve cell changes in HDC‐KO mice and their potential roles in TS to provide multiple directions for the future research on tics.

Small fiber neuropathy diagnosis

Small fiber neuropathies affect small, poorly myelinated sensory Aδ and amyelinated C autonomic fibers. Neuropathic pain is often the main symptom. Positive diagnosis is based on the presence of deficient thermo-algesic sensory signs and/or dysautonomic signs with normal neurography. Several tests help to confirm the involvement of small fibers, ranging from simple tests such as the sympathetic skin response to skin biopsy, which measures the density of intraepidermal nerve fibers. The availability of these different tests varies greatly from one center to another. There are multiple etiologies, from rare genetic causes to the more frequent acquired dysimmune or metabolic causes. However, in more than half of the cases, no etiology is identified.

Rare genetic causes of obesity: Diagnosis and management in clinical care

Rare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways. More than 60 genes coding for proteins located in the hypothalamic leptin/melanocortin pathway contribute to the development of these rare forms of obesity. The ambition of the French National Protocol for the Diagnosis and Care (PNDS) of Obesity of Rare Causes was to establish practical recommendations for assessment and management at all ages. This report is available on the website of the French Health Authority (HAS). In addition to severe obesity, patients often display obesity-related comorbidities and neuropsychological/psychiatric disorders. These complex conditions make clinical management particularly challenging. Early diagnosis is critical for the organization of coordinated specialized multidisciplinary care, with mandatory interaction between caregivers, social partners and families. Strategies to prevent aggravation of obesity consist in limiting access to food, establishing a reassuring daily eating environment, and the practice of sustained adapted supervised daily physical activity. The implementation of genetic diagnosis in clinical practice now enables a personalized medicine approach with access to new drug therapies, and improves the analysis of the risk/benefit ratio of bariatric surgery.

C56. Isolated Right Ventricular Non-Compaction Cardiomyopathy (IRVNC) in Adolescence: A Case Report

Abstract Background Non-compaction ventricular myocardium (NCVM) is a rare genetic cause of cardiomyopathy which mostly affects the left ventricle. A limited case of IRVNC was reported which render a limited knowledge for clinician. Case Summary A 16-y.o male presented to our emergency unit with recurrent syncope, chest discomfort, palpitation which exaggerated by strenuous exercise. There was no familial history of sudden death. On admission, BP of 102/64 mmHg and bradycardia of 49 bpm were remarkable. Electrocardiography revealed sinus arrhythmia, 49 bpm with early repolarization on precordial leads and LVH. Laboratory tests were in normal limits. Echocardiography revealed hyper-trabeculated RV with no LV-dysfunction. CMR was performed and showed normal LV dimension and function. Right atrium and RV were dilated with RV-dysfunction. RV trabeculae were indicative for IRVNC (NC/C ratio of 4.3). Holter ECG monitoring was done and remarkable for sinus arrhythmia without sinus pause nor ventricular arrhythmia. Anticoagulant was given for embolic prevention in the non-compacted area. ACEi, β-blockers, and diuretic were not given due to hypotension, bradycardia and no signs of congestion. The patient showed clinical improvement and discharged after 5 days of hospitalization. Discussions Recently, there has been no specific criteria and cut off for IRNVC. Earlier studies mentioned that ILVNC criteria could be used for diagnosing IRNVC, as we used in our case. In the future, it’s necessary to determine new cut off points dedicated for IRVNC. Furthermore, close follow-up is needed as complications such as arrhythmia, embolic events and heart failure might occurred.

C56. Isolated Right Ventricular Non-Compaction Cardiomyopathy (IRVNC) in Adolescence: A Case Report

Abstract Background Non-compaction ventricular myocardium (NCVM) is a rare genetic cause of cardiomyopathy which mostly affects the left ventricle. A limited case of IRVNC was reported which render a limited knowledge for clinician. Case Summary A 16-y.o male presented to our emergency unit with recurrent syncope, chest discomfort, palpitation which exaggerated by strenuous exercise. There was no familial history of sudden death. On admission, BP of 102/64 mmHg and bradycardia of 49 bpm were remarkable. Electrocardiography revealed sinus arrhythmia, 49 bpm with early repolarization on precordial leads and LVH. Laboratory tests were in normal limits. Echocardiography revealed hyper-trabeculated RV with no LV-dysfunction. CMR was performed and showed normal LV dimension and function. Right atrium and RV were dilated with RV-dysfunction. RV trabeculae were indicative for IRVNC (NC/C ratio of 4.3). Holter ECG monitoring was done and remarkable for sinus arrhythmia without sinus pause nor ventricular arrhythmia. Anticoagulant was given for embolic prevention in the non-compacted area. ACEi, β-blockers, and diuretic were not given due to hypotension, bradycardia and no signs of congestion. The patient showed clinical improvement and discharged after 5 days of hospitalization. Discussions Recently, there has been no specific criteria and cut off for IRNVC. Earlier studies mentioned that ILVNC criteria could be used for diagnosing IRNVC, as we used in our case. In the future, it’s necessary to determine new cut off points dedicated for IRVNC. Furthermore, close follow-up is needed as complications such as arrhythmia, embolic events and heart failure might occurred.

Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases.

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

Thyroid Disorders.

Thyroid Disorders.

Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum.

Are ICSI outcomes impaired in cases of severe asthenozoospermia with multiple morphological abnormalities of the flagellum (MMAF phenotype)? Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect. Severe asthenozoospermia, especially when associated with the MMAF phenotype, results in male infertility. Recent findings have confirmed that a genetic aetiology is frequently responsible for this phenotype. In such situations, pregnancies can be achieved using ICSI. However, few studies to date have provided detailed analyses regarding the flagellar ultrastructural defects underlying this phenotype, its genetic aetiologies, and the results of ICSI in such cases of male infertility. We performed a retrospective study of 25 infertile men exhibiting severe asthenozoospermia associated with the MMAF phenotype identified through standard semen analysis. They were recruited at an academic centre for assisted reproduction in Paris (France) between 2009 and 2017. Transmission electron microscopy (TEM) and whole exome sequencing (WES) were performed in order to determine the sperm ultrastructural phenotype and the causal mutations, respectively. Finally 20 couples with MMAF were treated by assisted reproductive technologies based on ICSI. Patients with MMAF were recruited based on reduced sperm progressive motility and increased frequencies of absent, short, coiled or irregular flagella compared with those in sperm from fertile control men. A quantitative analysis of the several ultrastructural defects was performed for the MMAF patients and for fertile men. The ICSI results obtained for 20 couples with MMAF were compared to those of 378 men with oligoasthenoteratozoospermia but no MMAF as an ICSI control group. TEM analysis and categorisation of the flagellar anomalies found in these patients provided important information regarding the structural defects underlying asthenozoospermia and sperm tail abnormalities. In particular, the absence of the central pair of axonemal microtubules was the predominant anomaly observed more frequently than in control sperm (P < 0.01). Exome sequencing, performed for 24 of the 25 patients, identified homozygous or compound heterozygous pathogenic mutations in CFAP43, CFAP44, CFAP69, DNAH1, DNAH8, AK7, TTC29 and MAATS1 in 13 patients (54.2%) (11 affecting MMAF genes and 2 affecting primary ciliary dyskinesia (PCD)-associated genes). A total of 40 ICSI cycles were undertaken for 20 MMAF couples, including 13 cycles (for 5 couples) where a hypo-osmotic swelling (HOS) test was required due to absolute asthenozoospermia. The fertilisation rate was not statistically different between the MMAF (65.7%) and the non-MMAF (66.0%) couples and it did not differ according to the genotype or the flagellar phenotype of the subjects or use of the HOS test. The clinical pregnancy rate per embryo transfer did not differ significantly between the MMAF (23.3%) and the non-MMAF (37.1%) groups. To date, 7 of the 20 MMAF couples have achieved a live birth from the ICSI attempts, with 11 babies born without any birth defects. The ICSI procedure outcomes were assessed retrospectively on a small number of affected subjects and should be confirmed on a larger cohort. Moreover, TEM analysis could not be performed for all patients due to low sperm concentrations, and WES results are not yet available for all of the included men. An early and extensive phenotypic and genetic investigation should be considered for all men requiring ICSI for severe asthenozoospermia. Although our study did not reveal any adverse ICSI outcomes associated with MMAF, we cannot rule out that some rare genetic causes could result in low fertilisation or pregnancy rates. No external funding was used for this study and there are no competing interests. N/A.

Novel Mutation of the TGF-β 3 Protein (Loeys-Dietz Type 5) Associated With Aortic and Carotid Dissections: Case Report.

ObjectivesLoeys-Dietz syndrome (LDS) is a rare genetic cause of stroke associated with connective tissue disorders but is not well known among stroke physicians.1 The main objectives of this case report are to increase awareness of this condition and to improve stroke prevention at follow-up visits.MethodsA patient with aortic and carotid artery dissection who had undergone 2 major aortic surgeries with mechanical composite graft and treated with full-dose anticoagulation was reevaluated by neurologists due to retinal hypoperfusion symptoms. After musculoskeletal examination, cervical ultrasonography, and computerized tomography angiography, he was referred for whole-genome sequencing.ResultsWe found joint hypermobility, skin hyperelasticity, bifid uvula, and combined cervical artery dissections that caused intermittently decreased blood flow in the left ophthalmic artery and an acute asymptomatic embolic stroke. A novel pathogenic variant of LDS type 5 consisting of a heterogeneous nonsense variant c.1044C>A, p.(Cys384*) was found in the TGF-β 3 (TGFB3) gene. Consequently, anticoagulation was intensified, and at 1-year follow-up, the patient's symptoms improved.DiscussionThis novel genetic variant coupled to the patient's phenotype contributes to the knowledge of genetic causes of stroke. Patients with multiple arterial dissections and musculoskeletal features should be offered genetic testing and be carefully evaluated to avoid further cerebrovascular ischemic lesions.

A rare case of male sex reversal syndrome (46, XX) with negative SRY gene: a disorder of sexual differentiation (DSD)

BackgroundMale sex reversal syndrome is a rare genetic cause of male infertility with an overall incidence of 1/20,000–1/100,000 males. There is mismatching between the genetic make-up and the apparent clinical features. The clinical presentation of such cases is variable ranging from ambiguous genitalia at birth, failed puberty, up to normal male phenotype with infertility and hypogonadism. The exact molecular and genetic bases of this syndrome are still unclear. Most of the recorded cases were SRY positive (i.e. representing 80–90% of all cases), and they showed translocated SRY gene on the Y chromosome. Moreover, fewer cases of male sex reversal (46, XX) were SRY negative.Case presentationHerby, we report a rare case of a 35-year-old infertile male patient who presented with azoospermia, hypergonadotropic hypogonadism, and abnormal classical (46, XX) karyotype, as well as negative FISH for SRY gene. He had a previous negative biopsy and was asking for redoing micro-TESE, whoever he was discouraged as chances to find sperm is eventually nil, and instead, he was prescribed testosterone replacement therapy to correct hypogonadism.ConclusionTherefore, any case of non-obstructive azoospermia should be offered genetic testing trying to exclude non-treatable cases and for genetic counseling.

P-PN036. Loss of function mutation in HINT1 gene presenting with neuromyotonia and hereditary neuropathy

Introduction. Histidine Triad Nucleotide binding protein 1 (HINT1) also known as Protein kinase C inhibitor 1 (PRKCNH-1); Protein kinase C interacting protein 1 (PKCI-1), mapped to chromosome 5q31, is a purine phosphoramidase homodimer and is ubiquitously expressed. HINT1 is a tumour suprresor gene and is involved in several apoptotic pathways. Biallelic variants in the HINT1 gene are known to cause Neuromyotonia with Axonal Neuropathy (NMAN). Zimon et al. have identified 8 HINT1 variants in 33 families of NMAN. Results. A 13-year-old male child, born of consanguineous parentage; presented for the first time in 2018 with of bilateral foot drop of 2 years duration. This was followed one and half year later by bilateral forearm and hand muscle weakness in the form of finger and wrist drop with ulner deviation of the wrist. Hyperpigmentation of the knuckles was noted on the examination. Investigations were negative for screening of inborn errors of metabolism by Tandem mass spectrometry. His serum vitamin B12 level was 692 pg/ml (180-914 pg/ml). ENMG demonstrated neurogenic myotonia. NGS of the proband reported a pathogenic start-loss variation c.3G>C_NM005340.7 (p.Met1Ile) in the HINT1 gene aligned to human reference genome (GRCh37/hg19). The variant is not reported in the ClinVar and the Human gemone mutation (HGMD) databases. A variant at c.2T>C has been reported as likely pathogenic for NMAN in the ClinVar database. The variant is reported as damaging by SIFT, possibly damaging by PolyPhen2, and disease causing by MutationTaster2. CADD score is 24. The variant is not reported in gnomAD, 1000 genome and ExAC population frequency databases. Conclusion. Rare genetic causes of CMT are important contributions to the full allelic spectrum of the disease. Here we report an ultra-rare NMAN case of Indian origin; mediated by a novel, pathogenic, biallelic start-loss variant in the HINT1 gene.

Small-expanded allele spinocerebellar ataxia 17: imaging and phenotypic variability.

Spinocerebellar ataxia 17 (SCA17) is a rare genetic cause of adult-onset ataxia caused by an abnormal expansion of the CAG/CAA sequence in the TATA-box Binding Protein (TBP) gene. A number of repeats higher than 49 are full penetrance-expanded. The range between 41 and 49 repeats is characterized by decreased penetrance, and it is usually referred to as "small." Here, we describe two patients with the SCA17 phenotype and with 43 and 44 CAG repeats in the TBP gene, and review all the previously reported cases of SCA17 with a small range of expansions. We focus on both clinical features and imaging findings, which, in the case of small-expanded alleles, can resemble those of atypical parkinsonisms. Thus, we suggest to consider the small-expanded allele SCA17 as a possible diagnosis in patients with adult-onset ataxia, even when both clinical and imaging characteristics are suggestive for other non-genetic neurodegenerative diseases.

Novel TUBA4A Variant Associated With Familial Frontotemporal Dementia.

ObjectiveDespite the strong genetic component of frontotemporal dementia (FTD), a substantial proportion of patients remain genetically unresolved. We performed an in-depth study of a family with an autosomal dominant form of FTD to investigate the underlying genetic cause.MethodsFollowing clinical and pathologic characterization of the family, genetic studies included haplotype sharing analysis and exome sequencing. Subsequently, we performed immunohistochemistry, immunoblotting, and a microtubule repolymerization assay to investigate the potential impact of the candidate variant in tubulin alpha 4a (TUBA4A).ResultsThe clinical presentation in this family is heterogeneous, including behavioral changes, parkinsonian features, and uncharacterized dementia. Neuropathologic examination of 2 patients revealed TAR DNA binding protein 43 (TDP-43) pathology with abundant dystrophic neurites and neuronal intranuclear inclusions, consistent with frontotemporal lobar degeneration–TDP type A. We identified a likely pathogenic variant in TUBA4A segregating with disease. TUBA4A encodes for α-tubulin, which is a major component of the microtubule network. Variants in TUBA4A have been suggested as a rare genetic cause of amyotrophic lateral sclerosis (ALS) and have sporadically been reported in patients with FTD without supporting genetic segregation. A decreased trend of TUBA4A protein abundance was observed in patients compared with controls, and a microtubule repolymerization assay demonstrated disrupted α-tubulin function. As opposed to variants found in ALS, TUBA4A variants associated with FTD appear more localized to the N-terminus, indicating different pathogenic mechanisms.ConclusionsOur findings support the role of TUBA4A variants as rare genetic cause of familial FTD.

Evolving Role of Patient Registries in Alport Syndrome

Alport syndrome is a relatively rare but important genetic cause of progressive kidney disease, sensorineural deafness and ocular abnormalities. Alport syndrome arises from genetic variants in the COL4A3, COL4A4 and COL4A5 genes, resulting in abnormal collagen IV networks in the basement membranes of the target organs. In the kidney, the basement membrane changes initiate a fibrotic cascade kidney failure. Our understanding of the natural history of Alport syndrome has been greatly enhanced by Alport syndrome registries, which have also generated insights that have helped to establish standards of care for the treatment of Alport kidney disease. Alport syndrome registries contribute to recruitment of participants in clinical trials of innovative therapies, and will in the future assist in monitoring the long-term outcomes associated with these novel approaches. This article reviews the history of Alport syndrome registries and discusses the opportunities and challenges facing these registries in the future.