Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis

ABSTRACTCongenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

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Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report

BMC Medical Genomics ◽

10.1186/s12920-020-00764-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Andrés López-Cortés ◽

Ana Karina Zambrano ◽

Patricia Guevara-Ramírez ◽

Byron Albuja Echeverría ◽

Santiago Guerrero ◽

...

Keyword(s):

Native American ◽

Case Report ◽

High Altitude ◽

Clinical Genomics ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

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Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis

Journal of International Medical Research ◽

10.1177/0300060517691699 ◽

2017 ◽

Vol 45 (2) ◽

pp. 549-555 ◽

Cited By ~ 3

Author(s):

Ting Wang ◽

Haibo Li ◽

Jingjing Xiang ◽

Bin Wei ◽

Qin Zhang ◽

...

Keyword(s):

Tyrosine Kinase ◽

Nonsense Mutation ◽

Mutation Screening ◽

Receptor Type ◽

Tyrosine Kinase Receptor ◽

Site Mutation ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron–exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

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Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: A splice junction mutation in intron 5 and cluster of four mutations in exon 15

Human Mutation ◽

10.1002/1098-1004(2001)17:1<72::aid-humu10>3.0.co;2-x ◽

2000 ◽

Vol 17 (1) ◽

pp. 72-72 ◽

Cited By ~ 19

Author(s):

Marek Bodzioch ◽

Katarzyna Lapicka ◽

Charalampos Aslanidis ◽

Marek Kacinski ◽

Gerd Schmitz

Keyword(s):

Tyrosine Kinase ◽

Splice Junction ◽

Receptor Type ◽

Tyrosine Kinase Receptor ◽

Gene Encoding ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

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Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis

Neuromuscular Disorders ◽

10.1016/j.nmd.2007.10.005 ◽

2008 ◽

Vol 18 (2) ◽

pp. 159-166 ◽

Cited By ~ 25

Author(s):

Kathrin Huehne ◽

Christiane Zweier ◽

Klaus Raab ◽

Sylvie Odent ◽

Martine Bonnaure-Mallet ◽

...

Keyword(s):

Tyrosine Kinase ◽

Receptor Type ◽

Tyrosine Kinase Receptor ◽

Deletion Mutations ◽

Insertion And Deletion ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

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Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1504447112 ◽

2015 ◽

Vol 112 (28) ◽

pp. 8696-8701 ◽

Cited By ~ 118

Author(s):

Fernanda S. G. Kehdy ◽

Mateus H. Gouveia ◽

Moara Machado ◽

Wagner C. S. Magalhães ◽

Andrea R. Horimoto ◽

...

Keyword(s):

Native American ◽

Latin American ◽

Middle Eastern ◽

Classical Model ◽

African Ancestry ◽

Genomic Analysis ◽

Genomic Diversity ◽

European Ancestry ◽

Eastern Region ◽

Whole Genome Analysis

While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6–8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.

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Novel Gross Deletion Mutations in NTRK1 Gene Associated With Congenital Insensitivity to Pain With Anhidrosis

Frontiers in Pediatrics ◽

10.3389/fped.2021.638190 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lulu Li ◽

Chao Jia ◽

Yue Tang ◽

Yuanyuan Kong ◽

Yaofang Xia ◽

...

Keyword(s):

Autosomal Recessive Disorder ◽

Recurrent Fever ◽

Tyrosine Kinase Receptor ◽

Compound Heterozygous ◽

Chinese Families ◽

Alu Elements ◽

Deletion Mutations ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis, recurrent fever, and intellectual disability. CIPA is mainly caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). This study aims to identify pathogenic mutations underlying CIPA in two unrelated Chinese families.Methods: DNA was extracted from blood samples of patients and their available family members and subjected to whole exome sequencing (WES). Real-time PCR (qPCR), Gap-PCR, and Sanger sequencing were applied to verify the identified variants.Result: We found novel compound gross deletion mutations [exon1-6 del (g.1-1258_10169del); exon5-7 del (g.6995_11999del)] of NTRK1 (MIM 191315) gene in family 1 and the compound heterozygous mutations [c.851-33T>A; exon5-7 del (g.6995_11999del)] in family 2. Interestingly, we discovered the intragenic novel gross deletion [exon5-7 del (g.6995_11999del)] mediated by recombination between Alu elements.Conclusions: The present study highlights two rare gross deletion mutations in the NTRK1 gene associated with CIPA in two unrelated Chinese families. The deletion of exon1-6 (g.1-1258_10169del) is thought to be the largest NTRK1 deletion reported to date. Our findings expand the mutation spectrum of NTRK1 mutations in the Chinese and could be useful for prenatal interventions and more precise pharmacological treatments to patients. WES conducted in our study is a convenient and useful tool for clinical diagnosis of CIPA and other associated disorders.

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Novel NTRK1 mutation in Chinese patient with congenital insensitivity to pain with anhidrosis: A Case Report

10.21203/rs.3.rs-17020/v1 ◽

2020 ◽

Author(s):

Jing Sha ◽

Zaochun Xu ◽

Jingfang Zhai ◽

Bei Zhang ◽

Yanling Zhang ◽

...

Keyword(s):

Case Report ◽

Novel Mutation ◽

Genetic Mutation ◽

Chinese Patient ◽

Tyrosine Kinase Receptor ◽

Sequencing Analysis ◽

Congenital Insensitivity ◽

In Silico Studies ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

Abstract Objective : Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessively inherited disorder characterized by insensitivity to noxious stimuli and inability to sweat. Methods : In this case report, an 18-year-old Chinese boy diagnosed with CIPA with the clinical features of loss of algesthesis, inability to sweat, self-mutilation, developmental delay and dislocation of the left hip joint. Blood samples from the patient was collected and subjected to genetic analysis. Results : Sequencing analysis revealed a novel mutation, c.1769A>G, in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1). In silico studies suggested that the mutations described are detrimental to the function of the protein encoded by the NTRK1 gene. Conclusions : The novel mutation widen the genetic mutation spectrum of NTRK1 in CIPA patients, and provide more evidence for precise diagnosis of the clinically suspected patients with CIPA.

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