Atypical features in two adult patients with Cockayne syndrome and analysis of genotype-phenotype correlation

To the Editor:Cockayne syndrome(CS;Mendelian Inheritance in Man#133540,216400)is a rare autosomal recessive neurodegenerative disorder described by Edward Cockayne in 1936.[1]The prevalence of CS is 2.7 per million live births,[2]and the disease is probably underdiagnosed.The major clinical features are progressive growth failure and microcephaly as well as other characteristics such as a“cachectic dwarfism”appearance with sunken eyes,cutaneous photosensitivity,mental retardation,demyelinating peripheral neuropathy,pigmentary retinopathy,cataracts,deafness,dental anomalies,and premature death.[1,3]There is considerable variation in the severity of the disorder,leading to classification into three main types.

Mutation Analysis of MR-1, SLC2A 1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients

Background： Paroxysmal kinesigenic dyskinesia （PKD） is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap. Methods： A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited, Clinical features were evaluated, and all subjects were screened for MR-l, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia （PNKD）, paroxysmal exertion-induced dyskinesia, and myotonia congenita （MC）, respectively, In addition, 200 genetically matched healthy individuals were recruited as controls. Results： A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G〉A mutation was detected in one case, and CLCN1 c. 1205C〉T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A 1 c.363G〉A mutation was novel. Conclusions： The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2-negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.

Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias

Background:Although many causative genes have been uncovered in recent years,genetic diagnosis is still missing for approximately 50%of autosomal recessive cerebellar ataxia(ARCA)patients.Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Methods:Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing(WES)and copy number variation(CNV)calling with ExomeDepth.Likely causal CNV predictions were validated by CNVseq.Results:Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients,providing a 46.3%positive molecular diagnostic rate.Ten different genes were involved,of which four most common genes were SACS,SYNE1,ADCK3 and SETX,which accounted for 76.0%(19/25)of the positive cases.The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide.Clinical features of the patients carrying SACS,SYNE1 and ADCK3 mutations were summarized.Conclusions:Our results expand the genetic spectrum and clinical profiles of ARCA patients,demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA,and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions

Proline-rich transmembrane protein 2(PRRT2)is the leading cause of paroxysmal kinesigenic dyskinesia(PKD),benign familial infantile epilepsy(BFIE),and infantile convulsions with choreoathetosis(ICCA).Reduced penetrance of PRRT2 has been observed in previous studies,whereas the exact penetrance has not been evaluated well.The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors.We screened 222 PKD index patients and their available relatives,identified 39 families with pathogenic or likely pathogenic(P/LP)PRRT2 variants via Sanger sequencing,and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature.Penetrance was estimated as the proportion of affected variant carriers.PRRT2 penetrance estimate was 77.6%(95%confidence interval(CI)74.5%–80.7%)in relatives and 74.5%(95%CI 70.2%–78.8%)in obligate carriers.In addition,we first observed that penetrance was higher in truncated than in non-truncated variants(75.8%versus 50.0%,P=0.01),higher in Asian than in Caucasian carriers(81.5%versus 68.5%,P=0.004),and exhibited no difference in gender or parental transmission.Our results are meaningful for genetic counseling,implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders,with patients from Asia or carrying truncated variants at a higher risk.

Genotype-phenotype correlations of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Background:Although many causative genes of hereditary spastic paraplegia(HSP)have been uncovered in recent years,there are still approximately 50% of HSP patients without genetically diagnosis,especially in autosomal recessive(AR)HSP patients.Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.Methods:In this study,we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing(NGS),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA).Further functional studies were performed to identify pathogenicity of those uncertain significance variants.Results:We identified 11 mutations in HSP related genes including 7 novel mutations,including two(p.V1979_L1980delinsX,p.F2343 fs)in SPG11,two(p.T55 M,p.S308 T)in AP5Z1,one(p.S242N)in ALDH18A1,one(p.D597fs)in GBA2,and one(p.Q486X)in ATP13A2 in 8 index patients and their family members.Mutations in ALDH18A1,AP5Z1,CAPN1 and ATP13A2 genes were firstly reported in the Chinese population.Furthermore,the clinical phenotypes of the patients carrying mutations were described in detail.The mutation(p.S242 N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55 M,p.S308 T)in AP5Z1 induced lysosomal dysfunction.Conclusion:Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

A Novel Missense Mutation in Peripheral Myelin Protein-22 Causes Charcot-Marie-Tooth Disease

Background：Charcot-Marie-Tooth disease （CMT） is the most common inherited peripheral neuropathy.A great number of causative genes have been described in CMT,and among them,the heterozygous duplication of peripheral myelin protein-22 （PMP22） is the major cause.Although the missense mutation in PMP22 is rarely reported,it has been demonstrated to be associated with CMT.This study described a novel missense mutation of PMP22 in a Chinese family with CMT phenotype.Methods：Targeted next-generation sequencing （NGS） was used to screen the causative genes in a family featured with an autosomal dominant demyelinating form of CMT.The potential variants identified by targeted NGS were verified by Sanger sequencing and classified according to the American College of Medical Genetics and Genomics standards and guidelines.Further cell transfection studies were performed to characterize the function of the novel variant.Results：Using targeted NGS,a novel heterozygous missense variant in PMP22 （c.320G〉A,p.G107D） was identified.In vitro cell functional studies revealed that mutant PMP22 protein carrying p.G 107D mutation lost the ability to reach the plasma membrane,was mainly retained in the endoplasmic reticulum,and induced cell apoptosis.Conclusions：This study supported the notion that missense mutations in PMP22 give rise to a CMT phenotype,possibly through a toxic gain-of-function mechanism.

A novel PCYT2 mutation identified in a Chinese consanguineous family with hereditary spastic paraplegia

Hereditary spastic paraplegia(HSP) is a rare neurodegenerative disease due to a length-dependent distal axonopathy of the corticospinal tract(Fink, 2006). HSP has highly clinical heterogeneity and is classified into pure and complex forms according to the description by Harding(1983).