Novel Mutations In TBC1D24 Associated With Epilepsy And Deafness:Report Of Two Cases

Background and Purpose: In the past ten years,people have gradually realized the multipotency of TBC1D24 gene,involving complex genotype-phenotype association.Different mutations can lead to different developmental disorders of nervous,hearing and skeletal systems,such as epilepsy,deafness,stunting and bone dysplasia.Early detection,early diagnosis and early intervention are important for the prognosis of patients.We report two unrelated Chinese patients with common clinical manifestations: epilepsy,sensorineural deafness and developmental retardation.By retrospective analysis of clinical data,laboratory tests and gene mutation results of 2 children with early epilepsy and deafness,the pathogenic mutations of two unrelated children were identified.To improve the understanding of the disease,to achieve early diagnosis and guide clinical treatment.Methods: Two children with early-onset epilepsy and deafness as the main clinical characteristics were selected as the subjects.Detailed clinical data were collected,including clinical manifestations,comprehensive physical examination,routine laboratory examination,impact study(brain MRI),electroencephalogram and metabolic study.The clinical data were analyzed retrospectively.At the same time,the peripheral blood of children,parents and brothers were collected,and the related epilepsy genes were selected for new generation sequencing(NGS)by referring to OMIM and HGMD databases.Confirmation of single nucleotide mutation results.Then,we use Poly Phen-2 software,ANNOVAR software,HGMD database,db SNP database,1000 Genome database for mutation annotation.Finally,Sanger method was used to validate the candidate mutation.Results: A female infant aged 58 days with refractory seizures was referred to our Center.The type of epileptic seizures is partial migratory seizures.Laboratory tests showed that the three routine indexes,liver and kidney function,myocardial enzymes and electrolytes were in normal range.There was no abnormality in the brain MR.There is a discrete discharge in the EEG.Auditory mechanics tests showed severe hearing impairment in both ears.Treatment with a variety of antiepileptic drugs such as topiramate,phenobarbital,levetiracetam,sodium valproate,there are still convulsions.This child has mental retardation and no developmental regression.The child eventually died of epileptic seizures.Gene sequencing revealed a heterozygous nucleotide variation in the TBC1D24 gene: c.116C>T(nucleotide No.116 of the coding region changed from C to T),c.827T>C(nucleotide No.827 of the coding region)Hybrid nucleotide variation from T to C).The former is inherited from the mother,the latter is passed on to the father.and the older brother is the carrier.Patient 2 was treated at Qingdao Women & Children's Hospital at the age of 1 year and 2 months.The onset age of the child is 3 months old.The form of seizures is complex focal myoclonus.The child was a premature infant with34+2 weeks and had a family history of febrile seizures.The child had no mental retardation before the onset of the disease.In his family history,her brother had a history of febrile convulsions.Only mild elevation of blood ammonia and lactic acid was detected in routine biochemical tests and metabolic studies.The EEG was normal.Head MRI showed bilateral ventricles full,bilateral cephalic space slightly wider,and the limited outer cerebral space slightly wider in the right cerebellar hemisphere.While we found that the child had a mild bilateral sensorineural hearing loss by using a brainstem auditory evoked potentials test.Epilepsy seizures were treated with levetiracetam,sodium valproate and clobazan,and convulsions could not be controlled.The frequency of epileptic seizures was about 2 times per month on average.The child had developmental retardation,and there was no regression problem.Compound heterozygous nucleotide variants were also found in TBC1D24 gene:c.404 C>T and c.679 T>C.Both of them were de novo missense mutations.The c.404 C>T leads to compile the 135 th amino acid Pro codon to Leu(p.Pro135Leu).The c.679 T>C change the 227 th amino acid from Arg to Trp(p.Arg227Trp).Conclusion: Poly Phen2,SIFT and Mutation Taster software were used to predict protein damage.These variations may lead to impairment of protein function.Complex heterozygous mutations(c.116C>T and c.827T>C;c.404C>T and c.679C>T)of TBC1D24 gene in two unrelated Chinese children can lead to a unique phenotype:epilepsy,deafness and developmental retardation.