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Journal canadien de la santé et de la maladie rénale
https://doi.org/10.1177/20543581231183856
Canadian Journal of Kidney Health
and Disease
Volume 10: 1 -10
© The Author(s) 2023
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DOI: 10.1177/20543581231183856
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Basic Research Protocol
1183856C JKXXX10.1177/20543581231183856Canadian Journal of Kidney Health and DiseaseSharma et al
research-article20232023
Basic Research Protocol: Exome
Sequencing in Adults With Loin Pain
Hematuria Syndrome: A Pilot Study
Aditi Sharma 1 , Matthew B. Lanktree 2,3 , Sarah Liskowich 4 ,
Pouneh Dokouhaki 5 , and Bhanu Prasad 6,7
Abstract
Background: Loin pain hematuria syndrome (LPHS) is a poorly understood clinical syndrome characterized by hematuria and
either unilateral or bilateral severe kidney pain in the absence of identifiable urological disease. Loin pain hematuria syndrome
imposes a significant health and economic impact with a loss of productivity and quality of life in a young population. Owing
to an incomplete understanding of its pathophysiology, treatment has been limited to nonspecific pain management. Nearly
60 years after its initial description, we are no further ahead in understanding the molecular pathways involved in LPHS.
Objective: To outline the study design for exome sequencing in adults with LPHS and their families.
Methods: In this single-center case series, 24 patients with LPHS and 2 additional first-degree family members per participant
will be recruited. DNA extracted from venous blood samples will undergo exome sequencing on the Illumina NovaSeq
6000 System at 100× depth and will be assessed for pathogenic variants in genes associated with hematuria (number of
genes in: glomerular endothelium [n = 10] and basement membrane [n = 8]), and pain pathways (number of genes in: pain
transduction [n = 17], conduction [n = 8], synaptic transmission [n = 37], and modulation [n = 27]). We will further
examine identified potentially pathogenic variants that co-segregate with LPHS features among affected families.
Conclusions: This pilot study may identify new directions for an investigation into the molecular mechanisms underlying
LPHS.
Abrégé
Contexte: Le syndrome de lombalgie-hématurie est un syndrome clinique encore mal compris qui se caractérise par une
hématurie et une forte douleur rénale unilatérale ou bilatérale en l'absence d'une maladie urologique identifiable. Le syndrome
de lombalgie-hématurie a une incidence importante sur la santé et l'économie en entraînant une perte de productivité et
de qualité de vie dans une population jeune. La compréhension de la physiopathologie de ce syndrome étant incomplète, le
traitement a été limité à la gestion non spécifique de la douleur. Près de soixante ans après sa description initiale, nous en
sommes au même point dans la compréhension des voies moléculaires impliquées dans le syndrome de lombalgie-hématurie.
Objectif: Décrire le plan de l'étude pour le séquençage de l'exome chez les adultes atteints du syndrome de lombalgie-
hématurie et des membres de leur famille.
Méthodologie: Pour cette série de cas menée dans un seul center, nous recruterons 24 patients atteints du syndrome de
lombalgie-hématurie et deux membres au premier degré de leur famille. L'ADN extrait d'échantillons de sang veineux sera
soumis à un séquençage de l'exome sur le système Ilumina NovaSeq 6000 réglé à 100X de profondeur. Il sera également
analysé pour la présence de variants pathogènes dans les gènes associés à l'hématurie (nombre de gènes dans l'endothélium
glomérulaire [n = 10] et la membrane basale [n = 8]), et aux voies de transmission de la douleur (nombre de gènes dans la
transduction [n = 17], la conduction [n = 8], la transmission synaptique [n = 37] et la modulation [n = 27] de la douleur).
Nous poursuivrons l'examen des variants potentiellement pathogènes identifiés qui co-ségrègent avec les caractéristiques du
syndrome de lombalgie-hématurie parmi les familles touchées.
Conclusion: Cette étude pilote pourrait révéler de nouveaux axes de recherche sur les mécanismes moléculaires qui sous-
tendent le syndrome de lombalgie-hématurie.
Keywords
loin pain hematuria syndrome, exome sequencing, rare disease, eGFR, hematuria, chronic pain
Received November 9, 2022. Accepted for publication May 18, 2023.
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+ 2
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+ Canadian Journal of Kidney Health and Disease
+
+ What was known before
Hematuria in patients with loin pain hematuria syndrome is
glomerular in origin, but the source of pain is a mystery.
What this adds
We outline our study protocol to investigate genetic variants
in the glomerular endothelium and basement membrane as
potential contributors to glomerular hematuria in LPHS. We
will also evaluate variants in candidate genes in pain path-
ways. We anticipate that the results from this study will iden-
tify new directions for an investigation into the molecular
mechanisms underlying LPHS pathophysiology.
Introduction
Loin pain hematuria syndrome (LPHS) remains a poorly
understood chronic pain disorder since its first description in
1967. 1 With a reported prevalence of .012%, 2 it typically
affects young women in their late 20s or early 30s. Patients
with LPHS experience debilitating flank (loin) pain, which
can be unilateral or bilateral, along with gross or microscopic
hematuria. 2,3 In 1996, Hebert et al proposed glomerular
hematuria as the instigating event, sequentially leading to
tubular obstruction, back leak of glomerular filtrate, and
local parenchymal edema promoting compression of adja-
cent tubules and subsequent capsular stretch leading to pain. 4
However, the absence of pain in other clinical conditions that
include red blood cell and cellular cast formation including
acute tubular necrosis (ATN), pyelonephritis, IgA nephropa-
thy (Henoch Schoenlein Syndrome), vasculitis, and antiglo-
merular basement membrane disease argues against the
validity of this mechanism. We believe LPHS likely repre-
sents a heterogeneous collection of cases that present with
shared phenotypic features of glomerular hematuria and pain
originating from the kidneys but with different pathogenesis
and natural history.
Glomerular hematuria in the absence of proteinuria is
typically associated with defects in the glomerular filtration
barrier, as most forms of podocyte injury lead to some degree
of proteinuria. The remaining structural components of the
filtration barrier include the glomerular basement membrane
(GBM) and the specialized fenestrated glomerular endothe-
lial cells (GEC). Glomerular basement membrane plays a
key role in keeping the cellular elements of blood from tres-
passing into the urinary space. The best technique to evaluate
GBM structure is electron microscopy of a kidney biopsy.
However, electron microscopy has not revealed structural
deficits in the GBM structure of most patient's with LPHS. 4
There is a real need for an enhanced understanding of
LPHS pathogenesis using advanced cellular and molecular
technologies to explicate, detect, and diagnose both its pres-
ence and probable outcome to treatment. Rapid advances in
next-generation sequencing (NGS) technologies over the last
2 decades have enabled the extensive unbiased interrogation
of the exome, with patient/parent trio being a successful
approach for identifying candidates and de novo variants.
Specifically, the trio exome analysis has added crucial
insights for diseases with complex pathogenesis and a heter-
ogenous rate of progressions, such as IgA nephropathy, 5 ste-
roid-resistant nephrotic syndrome, 6 nephrolithiasis, and
nephrocalcinosis. 7 In addition, for diseases like chronic kid-
ney disease (CKD) of unknown cause, where renal ultra-
sounds and kidney biopsies are uninformative and are unable
to distinguish between multiple diseases, exome sequencing
has led to the identification of 500 monogenic causes of
CKD, 8,9 which in turn led to an increased diagnosis rate. 10
Similarly, a phenotypic spectrum of GBM abnormalities has
been reported in patients with rare pathogenic variants in
type IV collagen genes (COL4A3/4/5), classically associated
with Alport syndrome, ranging from severe abnormalities in
GBM thickness to no visible abnormalities at all. The identi-
fication of more than 1000 mutations in the COL43/4/5
genes 11,12 that encode for the type IV collagen A3A4A5 het-
erotrimer (a major component of the GBM), has led to the
reclassification of Alport syndrome and benign familial
hematuria/thin basement membrane nephropathy (TBMN)
as type IV collagen nephropathies, 13 promoting genetic test-
ing as the gold standard in understanding the prognosis of the
phenotype. Therefore, we believe that the next logical step
will be to interrogate the genes that encode the filtration bar-
rier in patients with LPHS. There are 8 genes that encode
GBM and receptors and 10 genes that code for endothelial
cells that we know of to date. 14
While hematuria is believed to be glomerular in origin, the
genesis of the pain remains an unsolved issue. The transmis-
sion of pain from the viscera to the brain involves a pathway
that is controlled by a series of genes that code for transduc-
tion, conduction, synaptic transduction, and modulation.
Specialized receptors, expressed in the peripheral termini of
these neurons, allow noxious stimuli to be transduced into
electrical impulses. The local membrane depolarization gen-
erated by stimulus transduction is transmitted along the axon
by specific channels, some of which are expressed
+
+ 1 Dr. T. Bhanu Prasad Med Prof Corp, Regina, SK, Canada
2 Departments of Medicine and Health Research Methodology, Evidence,
and Impact, McMaster University, Hamilton, ON, Canada
3 Division of Nephrology, St Joseph's Healthcare Hamilton, ON, Canada
4 Department of Academic Family Medicine, College of Medicine,
University of Saskatchewan, Regina, Canada
5 Department of Pathology and Lab Medicine, University of Saskatchewan,
Saskatoon, Canada
6 Section of Nephrology, Department of Medicine, Regina General
Hospital, SK, Canada
7 College of Medicine, University of Saskatchewan, Regina, Canada
Corresponding Author:
Bhanu Prasad, Section of Nephrology, Department of Medicine, Regina
General Hospital, 1440, 14th Avenue, Regina, SK S4P 0W5, Canada.
Email: bprasad@sasktel.net
+
+ Sharma et al
+
+ 3
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+ specifically in nociceptors. Transmission is modulated by
specific channels, which generally act to reduce excitability.
Nociceptors terminate in the spinal cord dorsal horn, forming
synapses with nociceptive-specific spinal projection neurons.
From the spinal cord, information is transmitted to the brain
stem and then processed by a pain matrix in multiple brain
regions. Descending input from the brain to the spinal cord
back to the periphery can both inhibit and facilitate the trans-
mission of information in nociceptive circuits. We believe
that LPHS patients have either gain-of-function mutation of
the pain pathways and/or a loss-of-function mutation in the
pain dampening pathways. We hypothesize that rare variants
identified in this study will help delineate disease pathways
from a syndrome driven by clinically ascertained phenotype
as a diagnosis of exclusion into one based on the molecular
basis of disease that leads to hematuria and physically inca-
pacitating pain (Figure 1). To improve the sensitivity and
specificity to identify a responsible variant over singleton
analysis, we decided to perform a family-based analysis.
Exome sequencing will be performed in LPHS-affected pro-
bands and participating first-degree family members, to
effectively detect de novo and compound heterozygous vari-
ants. In the absence of parents, analysis will be performed on
the other family members such as siblings or cousins.
Systematic Review of Observational
Studies
We searched PubMed, Embase, Scopus and Web of Science
databases to identify published studies on LPHS (search term:
"loin pain hematuria" OR "Loin pain-hematuria" OR "loin
pain/haematuria" OR "loin pain haematuria"). The search
was generated in September 2021, with no date limits set. A
total of 110 articles were identified. Studies with no abstracts
or articles were excluded (n = 6). Upon review of 104 LPHS
articles included, encompassing 610 LPHS patients, with
68% of the articles and 87% of patients reported from the
United States and United Kingdom alone. With all articles
published so far focusing on symptomatic pain management
using oral narcotic therapy and/or interventional management
strategies such as intra-ureteric infusions, 15-17 surgical renal
denervation, 18-20 radiofrequency ablation, 21-23 neuromodula-
tion, 24-26 and auto-transplantation, 27-31 we did not identify any
studies looking at (A) evidence of familial clustering of LPHS
or its components, variability in prevalence across different
ancestries, or antecedent exposures or condition, or (B) vari-
ants in genes coding for proteins that are involved in GEC,
GBM, or the pain pathways.
Research Objectives
The specific objectives of the study are as follows:
Objective 1: Identify potentially pathogenic variants in
18 genes associated with hematuria 14 (Table 1).
Objective 2: Identify potentially pathogenic variants in
89 genes associated with pain syndromes 32 (Table 2).
Methods
We plan to conduct a single-center, pilot study with the aim
of decoding the molecular basis of LPHS. The study has
Figure 1. Study design.
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+ Canadian Journal of Kidney Health and Disease
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+ Table 1. Candidate Genes to be Investigated for Contributing to Hematuria in LPHS.
Gene name
Chromosome number
Inheritance a
Gene annotation
Glomerular basement membrane and receptors
LAMB2
chr3
AR
Laminin subunit beta 2
LAMA5
chr20
AR
Laminin subunit alpha 5
ITGA3
chr17
AR
Integrin subunit alpha 3
COL4A3/4/5
chr2/chr2/chrX
AR, AD/AR, AD/XLD
Collagen type IV alpha 3/4/5 chain
GPC5
chr13
Glypican 5
CD151
chr11
CD151 molecule -transmembrane 4 superfamily
Endothelial cells
CFH
chr1
AR, AD
Complement factor H
CFB
chr6
AR, AD, DD
Complement factor B
CFI
chr4
AR, AD
Complement factor I
C3
chr19
AR, AD
Complement C3
MCP
chr1
AR, AD
Membrane cofactor protein
THBD
chr20
AD
Thrombomodulin
PLG
chr6
AR, AD
Plasminogen
DGKE
chr17
AR
Diacylglycerol kinase epsilon
INF2
chr14
AD
Inverted formin 2
MMACHC
chr1
AR
Metabolism of cobalamin associated C
a
Inheritance based on OMIM database: AD, autosomal dominant; AR, autosomal recessive; Mu, multifactorial; SMu, somatic mutation; XL, X linked; XLR,
X linked recessive; XLD, X linked dominant
Table 2. Candidate Genes to be Investigated for Understanding Pain in LPHS Patients.
Gene name
Chromosome number
Inheritance a
Gene annotation
Pain transduction
TRPV1/2/3/4
chr17/chr17/chr17/chr12 TRPV3/4: AD
Transient receptor potential cation channel subfamily
V member 1/2/3/4
P2RX3
chr11
P2X purinergic receptor
TRPM8
chr2
Transient receptor potential cation channel subfamily
M member 8
TRPA1
chr8
AD
Transient receptor potential cation channel subfamily
A member 1
P2RY12
chr3
AR
Purinergic receptor P2y12
BDKRB1/2
chr14/chr14
Bradykinin receptor B1/2
HTR3a
chr11
5-Hydroxytryptamine receptor 3a
ACCN1/2
chr17/chr12
Acid sensing ion channel subunit 1/2
TRPC/P
chr13
Transient receptor potential canonical
Pain conduction
SCN10A
chr3
AD
Sodium voltage-gated channel alpha subunit 10
SCN11A
chr3
AD
Sodium voltage-gated channel alpha subunit 11
SCN1,3,8A
chr2/chr2/chr12
AD/AD/AD
Sodium channel protein type 1/3/8A
SCN9A
chr2
AR, AD
Sodium voltage-gated channel alpha subunit 9
KCNQ
chr11
AR, AD
Potassium voltage-gated channel subfamily Q
Pain synaptic transmission
NR1, 2
chr9/
AR, AD
Nuclear receptor subfamily 1/2
GRIA1-4
chr5/chr4/chrX/chr11
AR, AD/ AD/ XLR/ AD
AMPA receptor 1-4
NK1R
chr2
Tachykinin receptor 1
CACNA1A-I, S
chr19/chr9/chr12/chr3/
chr1/chrX/chr17/chr16/
chr22/chr1
AD/ AR/ AD/ AR, AD/ AD/
XL, XLR/ AD/ AD/ AD/ A
R, AD
Calcium voltage-gated channel subunit alpha1 A-S
CACNA2D1
chr7
AR
Calcium voltage-gated channel auxiliary subunit alpha2
delta 1
(continued)
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+ Sharma et al
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+ 5
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+ Gene name
Chromosome number
Inheritance a
Gene annotation
Pain modulation
BDNF
chr11
Brain-derived neurotrophic factor
OPRD1/M1/K1
chr1/ chr6/ chr8
Opioid receptor delta 1/Mu1/kappa 1
CNR1
chr6
Cannabinoid receptor 1
GABRs (GABRD/E/
P/Q/A1-A6/BR1-
BR3/G1-G3/R1-R3
chr1/chrX/chr5/chrX/chr5/
chr4/chrX/chr4/chr15/
chr5/chr4/chr5/chr15/
chr4/chr5/chr15/chr6/
chr6/chr3
AD/ M/ M/ M/ AD/ AD, Mu/
XL/ M/ AD/ M/ AD/AD/
AD/ M/ AD/ M/ M/ M/ M
Gamma-aminobutyric acid type A receptors
TNF
chr6
AD
Tumor necrosis factor
PLA2G2A
chr1
AD, SMu
Phospholipase A2
IL1/6/12/18
chr2/chr7/chr3/chr11
M/ Mu, SMu, AR, AD/ M/ M Interleukin 1/6/12/18
COX2
chrMT
Cytochrome C oxidase subunit 2
NTRK1
chr1
AR
High affinity nerve growth factor receptor
NGF
chr1
AR
Beta-nerve growth factor
GDNF
chr5
AD
Glial cell line-derived neurotrophic factor
LIF
chr22
AD
Leukemia inhibitory factor
CCL2
chr17
C-C motif chemokine 2
CNR2
chr1
Cannabinoid receptor 2
TLR2/4
chr4/chr9
AD, SMu/ M
Toll-like receptor 2/4
P2RX4/7
chr12/chr12
P2X purinoceptor 4/7
CX3CR1
chr3
CX3C chemokine receptor 1
a
Inheritance based on OMIM database: AD, autosomal dominant; AR, autosomal recessive; Mu, multifactorial; SMu, somatic mutation; XL, X linked; XLR,
X linked recessive; M, missing or no information in OMIM database.
Table 2. (continued)
been approved by the Saskatchewan Health Authority
Research Ethics Board (REB-22-66).
Design
Number of Subjects
Twenty-four LPHS patients referred to the nephrology clinic
(run by the corresponding author) were approached by the
study coordinator, and all 24 agreed to participate in the
study. Recruitment of 2 family members of the LPHS patient
(parents/siblings/cousins/children) is ongoing. We are the
first study to identify and report 2 patients with LPHS (12,
17) with a positive family history of LPHS (Figure 2). In
addition, 6 LPHS patients (LPHS: 01, 02, 04, 05, 11, and 21)
had a positive family history of intermittent hematuria
(Figure 2).
Duration of Study Period
The study period extended for about 3 years (2022-2025).
Participant Selection and Informed Consent
The LPHS patients have been identified by BP (Nephrologist)
and FG (Urologist), based on the inclusion and exclusion cri-
teria defined by Spetie et al 4 All patients and family mem-
bers that meet the eligibility criteria will need to complete
the written consent forms followed by baseline data collec-
tion (detailed below).
Inclusion criteria for LPHS patient
•
• ≥18 years of age
•
• Patients diagnosed with LPHS (by nephrologist and/
or urologist).
Exclusion criteria for LPHS patient
•
• Urological causes of flank pain and hematuria
(obstructive uropathy, nephrolithiasis, pyelonephritis,
polycystic kidney disease, renal artery embolism,
renal artery dissection, renal papillary necrosis, renal
vein thrombosis, left renal vein entrapment [nut-
cracker syndrome], renal trauma, or renal tumor).
•
• Additional functional/structural reason for hematuria
by kidney biopsy or other interventions.
Inclusion/exclusion criteria for family members
•
• Only family members (parents/siblings/children/first
cousin) of the patient who provide informed consent.
Data Collection, Sample Collection,
and Exome Analysis
Demographic Data
Data related to age, sex, gender, self-reported race/ethnic-
ity, occupation, socioeconomic status, weight, height,
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+ Canadian Journal of Kidney Health and Disease
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+ Figure 2. Pedigree of LPHS patients with a family history of LPHS or isolated hematuria (IH). Roman numbers represent the
generations of the family.
Note. Proband is indicated by arrow. Abbreviations: k, kidney stones; m, migraine.
comorbidities, family history of diseases (eg, kidney stones,
isolated hematuria, LPHS, diabetes, hypertension, chronic
fatigue syndrome, mood disorders, asthma, and allergies),
the location of pain (bilateral or unilateral), the number and
frequency of pain medications, and pain score using the brief
pain inventory form and PainDetect questionnaire will be
collected for the LPHS patients.
Laboratory Data
Complete blood count, serum electrolytes, serum urea and
creatinine, albumin creatinine ratio, and urine analysis.
Genetic Data
Rare variants in genes associated with hematuria (n = 18)
and in pain transduction (n = 17), conduction (n = 8), syn-
aptic transmission (n = 37), and pain modulation (n = 27).
Hierarchical Clustering of Patient Phenotype Data
Patients will be grouped based on their demographic, labora-
tory, and genetic data using unsupervised hierarchical clus-
tering (Ward's method with Euclidean distances). 33 The data
will be presented as clustered dendrograms.
Sample Collection, Storage, and Preparation
Venous blood samples will be collected for study probands
and participating family members in PAXgene Blood RNA
Tubes (Qiagen, Hilden, Germany). DNA will be extracted
from PAXgene Blood RNA Tube using the New England
Biolabs Monarch Genomic DNA Purification Kit as per the
protocol by Kruhøffer et al. 34 DNA libraries will be con-
structed using the Illumina DNA Prep with Enrichment,
Tagmentation kit and IDT xGen Exome Research Panel v2
with xGen Universal Blockers-NXT Mix and dual unique
+
+ Sharma et al
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+ 7
+
+ barcodes. Paired-end sequencing (2 × 150 bps) on the
Illumina NovaSeq 6000 System at 100× depth for exome
sequencing. Library preparation and sequencing will be per-
formed for all family members at the same time to minimize
potential artifactual differences due to sample preparation.
DNA samples will be stored at -80° centigrade to allow for
future verification studies.
Exome Analysis
As depicted in Figure 3, raw fastq files will be processed to
remove adapter sequences using cutadapt (v1.11). 35 Reads
with quality score of ≥30 will be retained for analysis.
Contaminating reads will be removed after aligning of the
processed reads to the human genome using BWA 36 and
Samtools. 37 The reads will be preprocessed using the
Genomic Analysis Tool Kit (GATK), as per the recommen-
dations in the Best Practices Workflow by the GATK 38 for all
positions with ≥20× coverage, genotype quality ≥20, and
minor read ratio ≥0.2 for indel alignment, base quality score
recalibration, base alignment quality scoring, and variant
calling (single-nucleotide variants [SNVs], indels, short tan-
dem repeats [STRs], structural variant [SV]). Variant allele
frequency (VAF) will be calculated as the percentage of
sequence reads observed for the alternative allele compared
to all coverage of that nucleotide. Exome data will first be
evaluated for genes associated with isolated hematuria and
pain (as listed in Tables 1 and 2). The variants will be further
filtered and prioritized using VarSeq software (Golden Helix,
Bozeman, MT, USA) and variant effect predictor. Benign
variants with MAF (minor allele frequency) >1% in any
ancestry will be eliminated using the 1000 Genomes
Project, 39 dbSNP, 40 gnomAD 41 and National Institutes of
Health (NIH)'s All of Us. 42 In silico bioinformatic prediction
of pathogenicity of variants will be performed using the fol-
lowing prediction algorithms: scale-invariant feature trans-
form (SIFT), 43 PolyPhen2, 44 Mutation Taster, 45 CADD, 46
VEST, 47 and FATHMM. 48 Finally, the candidate variants will
be checked against the human gene mutation database
(HGMD) 41 , LOVD, 12 Clinvar, 49 and Alport database. 50 A
multidisciplinary team will then review each variant for evi-
dence of pathogenicity and contribution to the phenotype
and classify them according to the American College of
Medical Genetics guidelines. 51 Possible pathogenic loci will
be screened according to 3 heredity models, namely autoso-
mal recessive (AR) inheritance, autosomal dominant (AD),
and X-linked inheritance. Sanger sequencing will be carried
out to validate potentially pathogenic variants identified
through high-throughput exome sequencing. Special atten-
tion will be paid to de novo variants, not present in parents,
as well as variants with variant allele frequencies suggestive
of potential somatic variation. Finally, we will also assess for
the presence of copy number variation using CoNIFER, 52
cn.MOPS, 53 and CNVkit. 54 To evaluate the pathogenicity of
a rare variant, we will look at the segregation of variants
among all sequenced family members using (A) probability-
based models by Helbig et al 55 and Jarvik et al, 56 and (B)
gene-based segregation methods. 57
Potential Risks to the Participants
In Canada, people are protected from being required to
provide the results of a genetic test by the Genetic Non-
Discrimination Act. 58 The genetic results will not be
Figure 3. Pipeline for exome data analysis.
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+ Canadian Journal of Kidney Health and Disease
+
+ disclosed to any third party such as employers, insurance
companies, or educational institutions. The confidentiality of
the participant will be respected. All collected samples will
be assigned a unique study number, with no reference to indi-
vidual identifiers. As this research involves looking at genetic
information, it carries the risk of identifying an underlying
genetic change(s) which are unrelated to this study and have
the potential of affecting the participant. However, this
research is being conducted for the scientific purpose of
understanding only the cause of pain and hematuria in LPHS
patients. In addition, the results of this research project will
not be placed in the participant's medical record. All efforts
will be made to safeguard participants' privacy.
+
+ Author Contributions
BP conceived and designed the study. AS wrote the initial draft.
ML and SL assisted with the drafts. ML provided advice regarding
genetic study design. BP edited the final manuscript. All authors
read and approved the final manuscript.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: BP has received speaker and advisory fees from Bayer,
Otsuka and Astra Zeneca. MBL has received speaker and advisory
fees from Otsuka, Reata, Bayer, and Sanofi Genzyme.
+
+ Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
author(s) received financial support for the research, authorship,
and/or publication of this article from the Hospitals of Regina
Foundation. MBL has funding support from CIHR project grant
(grant no. 201909-PJT). The funding sources had no role in the
design, conduct, and analysis of the study or in the decision to sub-
mit the manuscript for publication.
+
+ Ethics Approval and Consent to Participate
The study will be conducted in accordance with the second edition
of the Tri-Council Policy Statement-Ethical Conduct for Research
Involving Humans-TCPS 2. We have received REB certificate of
approval for the study (REB-22-66). Written informed consent will
be obtained from all the participants in the study.
Consent for Publication
Not applicable as there is no patient identifying information in this
article.
+
+ Availability of Data and Materials
The data sets used and/or analyzed during the current study are
available from the corresponding author on reasonable request.
+
+ ORCID iDs
Matthew B. Lanktree
https://orcid.org/0000-0002-5750-6286
Bhanu Prasad
https://orcid.org/0000-0002-1139-4821
+
+ References
1. Little PJ, Sloper JS, de Wardener HE. A syndrome of loin pain
and haematuria associated with disease of peripheral renal
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