Dataset Information

Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.

ABSTRACT: In families with autosomal dominant partial epilepsy with auditory features (ADPEAF) with mutations in the LGI1 gene, we evaluated clustering of mutations within the gene and associations of penetrance and phenotypic features with mutation location and predicted effect (truncation or missense).We abstracted clinical and molecular information from the literature for all 36 previously published ADPEAF families with LGI1 mutations. We used a sliding window approach to analyze mutation clustering within the gene. Each mutation was mapped to one of the gene's 2 major functional domains, N-terminal leucine-rich repeats (LRRs) and C-terminal epitempin (EPTP) repeats, and classified according to predicted effect on the encoded protein (truncation vs missense). Analyses of phenotypic features (age at onset and occurrence of auditory symptoms) in relation to mutation site and predicted effect included 160 patients with idiopathic focal unprovoked seizures from the 36 families.ADPEAF-causing mutations clustered significantly in the LRR domain (exons 3-5) of LGI1 (p = 0.026). Auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations (58% vs 80%, p = 0.018).The LRR region of the LGI1 gene is likely to play a major role in pathogenesis of ADPEAF.

SUBMITTER: Ho YY

PROVIDER: S-EPMC3280014 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.

Ho Yuan-Yuan YY Ionita-Laza Iuliana I Ottman Ruth R

Neurology 20120208 8

<h4>Objective</h4>In families with autosomal dominant partial epilepsy with auditory features (ADPEAF) with mutations in the LGI1 gene, we evaluated clustering of mutations within the gene and associations of penetrance and phenotypic features with mutation location and predicted effect (truncation or missense).<h4>Methods</h4>We abstracted clinical and molecular information from the literature for all 36 previously published ADPEAF families with LGI1 mutations. We used a sliding window approach ...[more]

PMID: 22323750

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Project description:The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodeficiency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two siblings who began to suffer from refractory diarrhea with a poor response to aggressive antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal obstruction. Their lymphocyte proliferation was low, but superoxide production and IL-10 signaling were normal. Candidate genetic approach targeted to genes involved in PIDs with inflammatory bowel disease (IBD)-like manifestation was unrevealing. Whole-genome sequencing revealed novel heterozygous mutations Glu75Lys and nucleotide 520-521 CT deletion in the tetratricopeptide repeat domain 7A (TTC7A) gene. A Medline search identified 49 patients with TTC7A mutations, of whom 20 survived. Their phenotypes included both multiple intestinal atresia (MIA) and combined T and/or B immunodeficiency (CID) in 16, both IBD and CID in 14, isolated MIA in 8, MIA, IBD, and CID complex in 8, and isolated IBD in 3. Of these 98 mutant alleles over-through the coding region clustering on exon 2 (40 alleles), exon 7 (12 alleles), and exon 20 (10 alleles), 2 common hotspot mutations were c.211 G>A (p.E71K in exon 2) in 26 alleles and AAGT deletion in exon 7 (+3) in 10 alleles. Kaplan-Meier analysis showed that those with biallelic missense mutations (p = 0.0168), unaffected tetratricopeptide repeat domains (p = 0.0311), and developing autoimmune disorders (p = 0.001) had a relatively better prognosis. Hematopoietic stem cell transplantation (HSCT) restored immunity and seemed to decrease the frequency of infections; however, refractory diarrhea persisted. Clinical improvement was reported upon intestinal and liver transplantation in a child with CID and MIA of unknown genetic etiology. In conclusion, patients with TTC7A mutations presenting with the very early onset of refractory diarrhea had limit improvement by HSCT or/and tailored immunosuppressive therapy in the absence of suitable intestine donors. We suggest that MIA-CID-IBD disorder caused by TTC7A mutations should also be included in the PID classification of "immunodeficiencies affecting cellular and humoral immunity" to allow for prompt recognition and optimal treatment.

Dataset Information

Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.

Publications

Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.

Similar Datasets

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