Novel compound heterozygous GPR56 gene mutation in a twin with lissencephaly:A case report

BACKGROUND Lissencephaly(LIS)is a malformation of cortical development with broad gyri,shallow sulci and thickened cortex characterized by developmental delays and seizures.Currently,20 genes have been implicated in LIS.However,GRP56-related LIS has never been reported.GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria.Here,we report a twin infant with LIS and review the relevant literature.The twins both carried the novel compound heterozygous GPR56 mutations.CASE SUMMARY A 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d.The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes.The electroencephalography was normal.Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci.The white matter of the brain was significantly reduced.Patchy long T1 and T2 signals could be seen around the ventricles,which were expanded,and the extracerebral space was widened.Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC(p.F76fs)and c.1820_1821delAT(p.H607fs).The unaffected father carried a heterozygous c.1820_1821delAT mutation,and the unaffected mother carried a heterozygous c.228delC mutation.The twin sister carried the same mutations as the proband.The patient was diagnosed with LIS.CONCLUSION This is the first case report of LIS that is likely caused by mutations of the GPR56 gene.

Crumbs homolog 2 mutation in two siblings with steroid-resistant nephrotic syndrome:Two case reports

BACKGROUND Crumbs homolog 2(CRB2)is a recently discovered gene that is closely related to the maintenance of normal polarity in podocytes;mutations can directly lead to steroid-resistant nephrotic syndrome(SRNS).However,the characteristics of nephrotic syndrome(NS)caused by CRB2 mutations have not been described.CASE SUMMARY We report a novel compound heterozygous mutation of the CRB2 gene in two siblings with SRNS.The two siblings had edema,proteinuria,hypoproteinemia and hyperlipidemia.Both their father and mother had normal phenotypes(no history of NS).Whole exon sequencing(WES)of the family showed a novel compound heterozygous mutation,c.2290(exon 8)C>T and c.3613(exon 12)G>A.Glucocorticoid therapy(methylprednisolone pulse therapy or oral prednisone)and immunosuppressive agents(tacrolimus)had no effect.During a 3-year follow-up after genetic diagnosis by WES,proteinuria persisted,but the patient was healthy.CONCLUSION CRB2 mutations related to SRNS often occur in exons 7,10,and 12.Clinical manifestations of SRNS caused by CRB2 mutations are often less severe than in other forms of SRNS.

Child with adenylosuccinate lyase deficiency caused by a novel complex heterozygous mutation in the ADSL gene:A case report

BACKGROUND Adenylosuccinate lyase(ADSL)deficiency is a rare autosomal-recessive defect of purine metabolism caused by mutation of the ADSL gene.It can cause severe neurological impairment and diverse clinical manifestations,including epilepsy.CASE SUMMARY Here,we describe a 3-year-old Chinese boy who had both psychomotor retardation and refractory epilepsy.Magnetic resonance imaging showed myelin hypoplasia.Electroencephalography findings supported a diagnosis of epilepsy.Whole-exon sequencing revealed the presence of a novel complex heterozygous mutation in the ADSL gene:The splicing mutation c.154-3C>G and the missense mutation c.71C>T(p.Pro24Leu).Considering the patient’s clinical presentation and genetic test results,the complex heterozygous mutation was predicted to prevent both ADSL alleles from producing normal ADSL,which may have led to ADSL deficiency.Finally,the child was diagnosed with ADSL deficiency.CONCLUSION We identified a novel complex heterozygous mutation in the ADSL gene associated with ADSL deficiency,thus expanding the known spectrum of pathogenic mutations that cause ADSL deficiency.Additionally,we describe epilepsy that occurs in patients with ADSL deficiency.

Autosomal recessive spinocerebellar ataxia type 4 with a VPS13D mutation:A case report

BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.

Epidermal growth factor receptor compound and concomitant mutations:advances in precision treatment strategies

Epidermal growth factor receptor(EGFR)mutations are common oncogenic driver mutations in patients with non-small cell lung cancer(NSCLC).The application of EGFR-tyrosine kinase inhibitors(TKIs)is beneficial for patients with advanced and early-stage NSCLC.With the development of next-generation sequencing technology,numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation;however,the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown.Thus,we review the incidence,prognosis,and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

Compound heterozygous mutation in two unrelated cases of Chinese spinal muscular atrophy patients

Background Infantile proximal spinal muscular atrophy （SMA） is a common autosomal recessive neuromuscular disorder. Approximately 90-95% cases of SMA result from homozygous deletion of survival motor neuron gene 1（SMN1） and 5% cases are caused by compound heterozygous mutation （a SMN1 deletion on one allele and a subtle mutation on the other allele）.Methods In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism （RFLP） and genomic sequencing. Multiplex ligation-dependent probe amplification （MLPA） analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein （NAIP） in the patients. Further sequencing of SMN1allele-specific PCR （AS-PCR） and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally,the pedigree analysis of these two families was carried out to identify the transmission of the mutation.Results The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G〉T （p. Arg288Met） mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN （SMN2 17/SMN1 E8） identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.Conclusion p. Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.

First-generation EGFR tyrosine kinase inhibitor therapy in 106 patients with compound EGFR-mutated lung cancer: a single institution’s clinical practice experience

Background:The antitumour efficacy of tyrosine kinase inhibitors(TKIs)in lung cancer patients with compound epidermal growth factor receptor(EGFR)mutations has not been resolved.Our study summarizes a single institutional experience of first-generation TKI therapy for lung cancers with compound EGFR mutations.Methods:A total of 106 consecutive patients with tumours bearing compound EGFR mutations were identified between January 2012 and May 2016;all patients received first-generation TKI therapy.Deletions in exon 19 and the L858R point mutation in exon 21 were considered common mutations;T790M was considered separately because of its association with TKIs resistances.Any other mutation was defined as a rare mutation.Patients were divided as follows:double common mutations(group A);common plus T790M mutations(group B);common plus rare muta-tions(group C);double rare mutations(group D);and rare plus T790M mutations(group E).A separate group of 115 consecutive patients with a single common mutation was created for comparative analysis(group F).Results:The frequency of patients with compound EGFR was 2.9%(114/3925)and their response rate to first-genera-tion TKIs was 50.9%,which was not significantly different from group F(67.0%,P=0.088).The progression-free survival(PFS)of the 106 patients receiving TKI therapy was worse than that of group F(median,9.1 vs.13.0 months,respec-tively;P<0.001).The PFS of the compound mutation group was shorter than that of the single common mutation group(median,10.1 months in group A,P=0.240;9.1 months in group B,P<0.001;9.6 months in group C,P=0.010;6.5 months in group D,P=0.048;5.4 months in group E,P=0.017).Patients with a co-occurring mutation in exon 20(excluding T790M)exhibited significantly worse PFS than the patients with other compound mutations or with a single common mutation(median,6.5 vs.9.1 vs.13.0 months,respectively,P=0.002).Conclusions:There was significant heterogeneity among the compound EGFR mutations and their response to first-generation TKIs.Individualized treatment in clinical practice should be considered for each case.

First cases of MPV17 related mitochondrial DNA depletion syndrome with compound heterozygous mutations in p.R50Q/p.R50W:a case report

Mutations in MPV17 lead to severe mitochondrial DNA depletion syndrome(MTDPS).All known p.R50W variants in MPV17 are lethal.The homozygous variant p.R50Q in MPV17 among patients with Navajo neurohepatopathy is known to allow longer survival,although heterozygous variants p.R50Q have not been reported.This is the first clinical report in compound heterozygosity MPV17 mutation(p.R50W/p.R50Q).Three siblings were admitted due to multiple hepatic nodules;none presented neurological abnormalities.However,they suffered from severe hypoglycemia and cyclic vomiting.The diagnosis of MPV17-related MTDPS was confirmed by detection of a compound heterozygous MPV17 mutation(p.R50W/p.R50Q),and striking reduction of hepatic mitochondrial DNA.One patient developed pediatric-onset of hepatocellular carcinoma.Notably,all patients survived for extended periods,including two patients who received liver transplantation,which contrasted the high mortality rate associated with p.R50W mutations,as previously reported.The p.R50Q mutation might be associated with longer survival and improved liver transplantation outcomes.