Mutation spectrum ofNOD2reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

AbstractInflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments.NOD2was the first and is the most replicated locus associated with adult IBD, to date. To determine the role ofNOD2and other genes in pediatric IBD, we performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands who were homozygous or compound heterozygous for rare and low frequencyNOD2variants accounting for approximately 8% of our cohort, suggesting a Mendelian recessive inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance ofNOD2alleles in adult IBD patients from the Regeneron Genetics Center (RGC)-Geisinger Health System DiscovEHR study, which links whole exome sequences to longitudinal electronic health records (EHRs) from 51,289 participants. We found that ~7% of cases in this adult IBD cohort, including ~10% of CD cases, can be attributed to recessive inheritance ofNOD2variants, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that 14% of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. Collectively, our findings show that recessive inheritance of rare and low frequency deleteriousNOD2variants account for 7-10% of CD cases and implicateNOD2as a Mendelian disease gene for early onset Crohn’s Disease.Author SummaryPediatric onset inflammatory bowel disease (IBD) represents ≥25% of IBD diagnoses; yet the genetic architecture of early onset IBD remains largely uncharacterized. To investigate this, we performed whole-exome sequencing and rare variant analysis on a cohort of 1,183 pediatric onset IBD patients. We found that 8% of patients in our cohort were homozygous or compound heterozygous for rare or low frequency deleterious variants in the nucleotide binding and oligomerization domain containing 2(NOD2)gene. Further investigation of whole-exome sequencing of a large clinical cohort of adult IBD patients uncovered recessive inheritance of rare and low frequencyNOD2variants in 7% of cases and that the relative risk forNOD2variant homozygosity has likely been underestimated. While it has been reported that having >1NOD2risk alleles is associated with increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate what has long been suspected: recessive inheritance ofNOD2alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Our data suggest that a subset of IBD-CD patients with early disease onset is characterized by recessive inheritance ofNOD2alleles, which has important implications for the screening, diagnosis, and treatment of IBD.

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Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

Scientific Reports ◽

10.1038/s41598-021-84938-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Julie E. Horowitz ◽

Neil Warner ◽

Jeffrey Staples ◽

Eileen Crowley ◽

Nehal Gosalia ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Protein Function ◽

Early Onset ◽

Low Frequency ◽

Mendelian Inheritance ◽

Clinical Population ◽

Mendelian Disease ◽

Recessive Inheritance ◽

Pediatric Onset

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Whole-exome sequencing identifies compound heterozygous LHX4 mutations in a fetus with early-onset growth restriction

European Journal of Obstetrics & Gynecology and Reproductive Biology ◽

10.1016/j.ejogrb.2017.02.025 ◽

2017 ◽

Vol 211 ◽

pp. 225-227

Author(s):

Yue-Cheng Lu ◽

Lv-Ying Huang ◽

Jin-Mei Yan ◽

Yi Zhang ◽

Dong-Zhi Li

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Growth Restriction ◽

Compound Heterozygous ◽

Whole Exome

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Understanding What You Have Found: A Family With a Mutation in the LAMA1 Gene With Literature Review

Clinical Medicine Insights Case Reports ◽

10.1177/1179547620948666 ◽

2020 ◽

Vol 13 ◽

pp. 117954762094866

Author(s):

Muhsin Elmas ◽

Basak Gogus ◽

Mustafa Solak

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Imaging Finding ◽

Large Data ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Sequencing Analysis ◽

Recessive Inheritance ◽

Data Generation ◽

Whole Exome

Introduction: Cerebellar dysplasia with cysts (CDC) is an imaging finding which is typically seen with in individuals with dystroglycanopathy. One of the diseases causing this condition is “Poretti-Boltshauser Syndrome; PTBHS” (OMIM #615960). Homozygous or compound heterozygous mutations in the LAMA1 gene cause this disease. Case presentation: 7 years old twin siblings consulted to the medical genetics department because of walking problems and cerebellar examination findings. Management and Outcome: Clinical and radiological findings of the patient suggested a syndrome with recessive inheritance. Whole exome sequencing (WES) test was performed for definitive diagnosis. As a result of the patient’s WES analysis, a homozygous mutation was detected in the LAMA1 gene. Discussion: When determining the inheritance pattern of genetic diseases, if parents have consanquinity, this situation leads us to recessive inheritance diseases. Even if we are not consanquinity, but they say the same village, it is necessary to pay attention to the diseases of the recessive group. Whole exome sequencing analysis results in large amount of data generation. A good clinical evaluation is required to detect the mutation as a result of large data. To understand what we have found, we need to know what we are looking for.

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Whole exome sequencing identified a new compound heterozygous PRKN mutation in a Chinese family with early-onset Parkinson’s disease

Bioscience Reports ◽

10.1042/bsr20200534 ◽

2020 ◽

Vol 40 (5) ◽

Author(s):

Tianbai Li ◽

Daqing Kou ◽

Yanhua Cui ◽

Weidong Le

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Chinese Family ◽

Compound Heterozygous ◽

Therapy Strategy ◽

Whole Exome ◽

Early Onset Parkinson’S Disease

Abstract Early-onset Parkinson’s disease (EOPD) is usually caused by genetic variants and patients with EOPD develop symptoms before the age of 50, accounting for 5% Parkinson’s disease (PD). Here we present a Chinese Han pedigree with clinical features of EOPD. To determine the diagnosis and pathogenic mutations of this pedigree, whole exome sequencing, Sanger sequencing and real-time quantitative PCR were performed to detect all the four family members. Our results showed that a new form of compound heterozygous mutation in the PRKN gene, consisting of heterozygous point mutation c.850G > C (p.G284R) along with exon 4 deletion, is the causative genetic factor for EOPD in this pedigree. These discoveries may have implications for genetic counseling, clinical management and developing PRKN target gene therapy strategy.

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The role of recessive inheritance in early-onset epileptic encephalopathies: a combined whole-exome sequencing and copy number study

European Journal of Human Genetics ◽

10.1038/s41431-018-0299-8 ◽

2018 ◽

Vol 27 (3) ◽

pp. 408-421 ◽

Cited By ~ 15

Author(s):

Sorina M. Papuc ◽

Lucia Abela ◽

Katharina Steindl ◽

Anaïs Begemann ◽

Thomas L. Simmons ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Copy Number ◽

Recessive Inheritance ◽

Epileptic Encephalopathies ◽

Whole Exome

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Whole exome sequencing of patients who resolved Crohn’s disease and complex regional pain syndrome following treatment for paratuberculosis

Gut Pathogens ◽

10.1186/s13099-019-0311-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

J. Todd Kuenstner ◽

Maher Kali ◽

Christine Welch

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Complex Regional Pain Syndrome ◽

Whole Exome Sequencing ◽

Pain Syndrome ◽

Whole Exome

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Tubulin Folding Cofactor D Deficiency: Missing the Diagnosis With Whole Exome Sequencing

Child Neurology Open ◽

10.1177/2329048x211034969 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110349

Author(s):

Christina M. Quitmann ◽

Stephan Rust ◽

Janine Reunert ◽

Saskia Biskup ◽

Barbara Fiedler ◽

...

Keyword(s):

Neurodegenerative Disease ◽

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

Early Onset ◽

Compound Heterozygous ◽

Muscular Hypotonia ◽

Gene Coding ◽

Whole Exome ◽

First Time

Two siblings with an early onset of a neurodegenerative disease were presented with muscular hypotonia, secondary microcephaly, and severe developmental delay. Seizures were refractory to treatment but could be controlled with a ketogenic diet. Over the course of 5 years, whole exome sequencing (WES) was performed twice in both children. The first time the diagnosis was missed. The next one revealed compound heterozygous mutations in the gene coding for the tubulin folding cofactor D. Technical improvements in WES mandated a new investigation after a few years in children where the diagnosis has not been found.

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DOP36 Family-specific host genetic and gut microbial signatures have a beneficial role in early identification of familial inflammatory bowel diseases

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.075 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S073-S074

Author(s):

G Y SHIN ◽

Y M Park ◽

E Ha ◽

K N Gu ◽

K Kim ◽

...

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Identification ◽

Beneficial Role ◽

Specific Host ◽

Whole Exome ◽

Host Genetic

Abstract Background Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles. Methods All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples. Results Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p < 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p < 0.05; Figure 2). Conclusion Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).

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