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

Abstract

Background: Congenital 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). Case presentation: Here, we present clinical and molecular findings in a 9-year-old girl with CIPA. The highaltitude indigenous Ecuadorian patient presented several health problems such as anhidrosis, bone fractures, selfmutilation, osteochondroma, intellectual disability and Riga-Fede disease. After the mutational analysis of NTRK1, the patient showed a clearly autosomal recessive inheritance pattern with the pathogenic mutation rs763758904 (Arg602*) and the second missense mutation rs80356677 (Asp674Tyr). Additionally, the genomic analysis showed 69 pathogenic and/or likely pathogenic variants in 46 genes possibly related to phenotypic heterogeneity, including the rs324420 variant in the FAAH gene. The gene ontology enrichment analysis showed 28 mutated genes involved in several biological processes. As a novel contribution, the protein-protein interaction network analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix involved in the response to stimulus and nervous system development. Conclusions: This is the first study that associates clinical, genomics and networking analyses in a Native American patient with consanguinity background in order to better understand CIPA pathogenesis.

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature

“…was inherited from his father, and the missense variant, c.2020G>T (p.Asp674Tyr), classified as likely pathogenic by ACMG classification, was inherited from his mother. c.2020G>T (p.Asp674Tyr) has also been reported previously (López‐Cortés et al., 2020). In patient 3, compound heterozygous variants c.2303C>T (p.Pro768Leu) and c.574‐156_850+1113del (exons 5‐7 del) were identified.…”

“…The frequency of this variant is extremely low in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041, PM2). It has been observed as a compound heterozygote with other variants, suggesting the attenuated nature of this variant (López‐Cortés et al., 2020; Miranda, Di Virgilio, et al., 2002; Miura et al., 2000). The alternative variant situated in the tyrosine kinase domain, c.2303C>T (p.Pro768Leu), was documented to exhibit milder symptoms with retained cognitive function and pain sensation (Jung et al., 2013; Ohto et al., 2004; Tanaka et al., 2012).…”

Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

“…An early disease onset in 5q SMA types I and 0 illustrates the imperative need for implementing the aforementioned up-to-date strategies that might include newborn or even prenatal SMA genetic screening. Quantitative real time PCR (qPCR) seems to be an effective method for genetically testing newborns [ 7 , 145 , 146 ]. At present, nine countries have implemented SMA newborn screening (NBS) programs, Taiwan and the US being the leading nations with 90% and 70% of newborns screened for SMA, respectively [ 4 ].…”

Ophthalmic findings of congenital insensitivity to pain with anhidrosis with a novel neurotrophic tyrosine kinase receptor type 1 gene mutation: A case report

“…At the same time, insensitivity to pain and thermal sensations could lead to multiple fractures, burns and sometimes self-mutilation of fingers, tongue, and lips. Autonomic dysfunction leads to manifestations like anhidrosis and fever ( 4 , 5 ). In recent years, with the accumulation of clinical experience and the development of genome sequencing technology, it has been found that the recessive mutation of NTRK1 may lead to CIPA.…”