Clinical features and CACNA1A gene mutation in a family with episodic ataxia type 2 / 中南大学学报(医学版)

Episodic ataxia (EA) is a group of disorders characterized by recurrent spells of vertigo, truncal ataxia, and dysarthria. Episodic ataxia type 2 (EA2), the most common subtype of EA, is an autosomal dominant disease caused by mutation of the CACNA1A gene. EA2 has been rarely reported in the Chinese population. Here we present an EA2 family admitted to Xiangya Hospital in October 2018. The proband was a 22-year-old male who complained of recurrent spells of vertigo, slurred speech, and incoordination for 4 years. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy. He had neuropsychological development disorder in childhood, and cognitive assessment in adulthood showed cognitive impairment. The proband's mother and grandmother had a similar history. Peripheral blood samples from the proband and family members were collected, and genomic DNA was isolated. Whole exome sequencing of the proband detected a heterozygous frameshift mutation c.2042_2043del (p.Q681Rfs*100) of CACNA1A gene. This mutation was verified in the proband and 2 family members using Sanger sequencing. One family member carrying this mutation was free of symptoms and signs, suggesting an incomplete penetrance of the mutation. We reported a variant c.2042_2043del of CACNA1A gene as the pathogenic mutation in a Chinese EA2 family for the first time. This case enriched the clinical spectrum of CACNA1A related EA2, and contributed to the understanding of clinical and genetic characteristics of EA2 to reduce misdiagnosis.

A case of ADULT syndrome without finger/toe deformities caused by a TP63 mutation / 中华皮肤科杂志

Objective:To detect causative gene mutations in 1 patient with ADULT syndrome mainly presenting with ectodermal dysplasia.Methods:Clinical data were collected from a proband with ADULT syndrome, and genomic DNA was extracted from peripheral blood samples obtained from the proband and his parents. Exome sequencing was performed in the proband by using targeted panels for hereditary skin diseases to determine mutation sites, and then the candidate mutation sites were verified by Sanger sequencing in the family members.Results:The 22-year-old male patient presented with sparse and thin hair, scattered facial freckles, missing permanent teeth, cloudy corneas, palmoplantar erythema and keratosis, nail/toenail dystrophy, and nipple dysplasia. Genetic testing of the peripheral blood genomic DNA of the proband revealed a heterozygous mutation (c.1040G>T) in exon 8 of the TP63 gene, resulting in an amino acid change at position 347 (p.C347F) . The mutation was not detected in his father or mother with normal phenotypes, suggesting the cosegregation of the gene mutation with the disease phenotype in the family.Conclusion:The de novo heterozygous missense mutation in the TP63 gene may be the causative mutation in the proband, and combined with clinical manifestations, the proband was diagnosed with ADULT syndrome without finger/toe deformities.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions / 医学前沿

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.

Low-penetrance susceptibility variants and postmenopausal oestrogen receptor positive breast cancer

The risk of breast cancer (BC) in women is high and many factors including genetic factors increase the risk for the disease. It is revealed that the variations of low-penetrance susceptibility genes are important for carcinogenesis as they interact with the environmental and hereditary factors. Recently, the list of BC-associated common single nucleotide polymorphisms (SNPs) and chromosomal loci in low-penetrance susceptibility genes have been expanded in genomewide association studies. FGFR2, LSP1, MAP3K1, TGFB1, TOX3, 2q35 and 8q loci variations are some examples for these common SNPs. These SNPs and their association with BC risk was investigated in many different populations. Therefore in this study, we aimed to evaluate low-penetrance susceptibility SNPs; namely FGFR2 rs1219648, rs2981579, rs2981582; MAP3K1 rs889312; TOX3 rs3803662; LSP1 rs909116, rs3817198 and SLC4A7 rs4973768 together, for the first time in Turkish postmenopausal oestrogen receptor positive BC cases. Following the DNA isolation, multiplex PCR and matrix-assisted laser desorption/ionization mass spectrometry with time of flight measurement (MALDI-TOF) based SNP analysis were performed. MAP3K1 rs889312 SNP demonstrated the strongest association with BC risk among the other low penetrant SNPs, it was also associated with BC risk in a dominant model. Only in a ressesive model, TOX3 rs3803662 was associated with BC risk. In addition, rs4973768 CC and rs909116 CC genotypes are correlated with higher tumour size which is not reported in the literature as yet; on the other hand there are no associations between any of the other SNP genotypes and clinopathological parameters. In our opinion, MAP3K1 rs889312 may be a good BC susceptibility biomarker candidate for Turkish population.

Observation of penetrance and retinal nerve fiber layer and macular thickness in patients with Leber's hereditary optic neuropathy / 中华眼底病杂志

Objective To observe the effects of penetrance,different time of onset and mutation sites on retinal nerve fiber layer (RNFL) and macular thickness in patients with Leber's hereditary optic neuropathy (LHON).Methods This was a cross-sectional observational study.A total of 88 patients with LHON and 1492 relatives of the maternal relatives (gene carriers) who received treatment in People's Liberation Army General Hospital from 2015 to 2017 were included in the study.Among the 1492 family members,there were 694 males and 798 females.Peripheral venous blood was extracted from all subjects for mitochondrial DNA testing,and penetrance was calculated.A total of 117 patients underwent BCVA and SD-OCT examinations,including 82 patients and 35 gene carriers.The BCVA examination was performed using the Snellen visual acuity chart,which was converted into logMAR visual acuity.The thickness of RNFL,ganglion cell complex (GCC) and inner limiting membrane (ILM)-RPE were measured with OCT instrument.The mean follow-up was 50.02± 86.27 months.The disease course was divided into 6 stages including ≤3 months,4-6 months,7-12 months and ＞ 12 months.The thickness of RNFL,GCC and ILM-RPE in patients with different time of onset and mutation sites were comparatively analyzed by covariance analysis.Categorical variables were expressed as a percentage,and the x2 test was used for comparison among multiple groups.Results Among the 1492 family members,285 were diagnosed with LHON and highly suspected clinical manifestations (19.10％),including 190 males (21.98％) and 95 females (11.90％).The total penetrance rates of 11778,14484 and rare mutation sites were 19.84％ (228/1149),20.50％ (33/161),and 13.19％ (24/182) respectively;male penetrance rates were 28.87％ (153/530),27.28％ (20/72),and 18.48％ (17/92) and female penetrance rates were 12.12％ (75/619),14.61％ (13/89) and 7.78％ (7/90).There was no significant difference in total (x2=4.732),male (x2=4.263) and female (x2=4.263) penetrance between different mutation sites (P=0.094,0.110,0.349).Compared with non-pathogenic carriers,the thickness of the RNFL,GCC and ILM-RPE were all different in the four stages (≤3months,4-6 months,7-12 months and ＞12 months).The thickness ofRNFL,GCC and ILM-RPE decreased with the time of onset (P=0.000).There were significant differences in the thickness of each of the GCC and ILM-RPE layers in the macular area of LHON patients with different mutation sites (P＜ 0.05).Among them,the site 11778 and 3460 had the most severe damage in all quadrants of macular GCC and ILM-RPE layer,followed by 14484 site,and the rare site had the least damage in all quadrants.Conclusions The penetrance of LHON patients is 19.10％.With the extension of the onset time (within 1 year),the RNFL layer of the optic disc and all quadrants of the macular GCC and ILM-RPE layer gradually thinned.Compared with 11778 and rare site,14484 site,and the rare site had the lighter damage on the thickness of RNFL,GCC and ILM-RPE.

Breast cancer risk in BRCA1 and BRCA2 mutation carriers in Chinese Han population / 中国癌症杂志

Background and purpose: BRCA1 and BRCA2 mutation carriers have a high lifetime risk of developing breast and ovarian cancer. Through genetic counseling, mutation carriers can take the appropriate measures to reduce such cancer risk. At present, almost all related studies were conducted in Caucasian, while, the studies in Chinese population were rare. This study aimed to investigate the risk of breast cancer in BRCA1 and BRCA2 mutation carriers in Chinese Han population. Methods:Twenty unrelated families with BRCA1 or BRCA2 mutations were re-viewed. Kaplan-Meier analyses were used to estimate the cumulative risks of unilateral breast cancer and contralateral breast cancer for female BRCA1 and BRCA2 mutation carriers. Results:Breast cancer risk to 70 years (penetrance) was 67.2%(sx 0.100) for BRCA1 and 76.8%(sx 0.079) for BRCA2, respectively. Different from BRCA1 mutation carriers, the cumulative incidence of breast cancer in BRCA2 mutation carriers remained increasing after 70 years, reaching 93.1%at age 80. The 10-and 20-year risk for contralateral breast cancer was 19.4%(sx 0.089) and 50.3%(sx 0.155) for BRCA1/2 mutation carriers. Conclusion:BRCA1 and BRCA2 mutation carriers in Chinese Han population have a high risk of developing breast cancer. Thus, it has great clinical signiifcance to test mutations in BRCA1/2 genes in Chinese high-risk population.

A Case of Late-Onset Li-Fraumeni-like Syndrome with Unilateral Breast Cancer

Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.

A Case of Late-Onset Li-Fraumeni-like Syndrome with Unilateral Breast Cancer

Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance.

PENCALC: a program for penetrance estimation in autosomal dominant diseases

We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95 percent credibility interval for the penetrance estimate. Both executable (PenCalc for Windows) and web versions (PenCalcWeb) of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

Identificación de genes causales y de susceptibilidad para enfermedades de herencia mendeliana y compleja / Identification of susceptibility and causing genes for mendelian and complex diseases

Los factores genéticos participan en la etiología de la mayoría de las enfermedades comunes en la población. Las enfermedades en las que participan factores genéticos pueden ser clasificadas en varias categorías y de acuerdo con las características que presenten, se pueden utilizar distintas estrategias metodológicas para identificar los genes participantes. En la mayoría de las enfermedades con un patrón de herencia mendeliana, se han podido identificar las mutaciones causales de la enfermedad. En las enfermedades complejas, esta búsqueda ha sido menos exitosa a pesar de ser las más frecuentes en la población. Encontrar genes de susceptibilidad es importante no solo para entender el mecanismo de acción de la enfermedad, sino que podría contribuir en el desarrollo de medicamentos más eficaces para el tratamiento, conocer los factores ambientales y desarrollar intervenciones preventivas y, en algunos casos, la aplicación de terapia génica.

Genetic factors are involved in the etiology of most common diseases and traits present in populations. Different methodological approaches can be utilized to determine genes involvedaccording to their genetic features in diseases. In the majority of conditions that follow a simple Mendelian pattern culprit genetic mutations have been identified. Conversely complex traits that are most common in the population are also the most difficult to identify. Finding these genes is crutial no just to clarify the pathophysiology of these common diseases but also to identifyenvironmental factors involved and to improve their treatment, including in some specific cases gene therapy.

The Breast and Ovarian Cancer Risks in Korea Due to Inherited Mutations in BRCA1 and BRCA2: A Preliminary Report / 한국유방암학회지

PURPOSE: To estimate the cumulative risk till each age (penetrance) of breast and ovarian cancers among female family members with BRCA1 and BRCA2 mutation. METHODS: Among the 61 BRCA1 mutation carriers in the 42 families and 47 BRCA2 mutation carriers in 31 families identified at 5 academic breast clinics, the probands were excluded to estimate the cumulative risk till each age of breast cancer in the Korean BRCA1 and BRCA2 carriers. Using Kaplan-Meier analyses, cumulative cancer risk estimates were determined. RESULTS: By the age 70, the female breast cancer risk for the BRCA1 and BRCA2 mutation carriers was 72.1% (95% confidence interval [CI]=59.5% to 84.8%) and 66.3% (95% CI=41.2% to 91.5%), respectively, and the ovarian cancer risk was 24.6% (95% CI=0% to 50.3%) and 11.1% (95% CI=0% to 31.6%), respectively. The contralateral breast cancer risk at 5 years after primary breast cancer was estimated as 16.2% (95% CI=9.3% to 23.1%) for the 52 breast cancer patients with the BRCA1 mutation and 17.3% (95% CI=9.7% to 24.0%) for the 35 breast cancer patients with the BRCA2 mutation. CONCLUSION: The penetrance of BRCA mutations in Korea is largely consistent with the previous studies on Western populations. However, the small number of the cases, the high proportions of probands in the study subjects, the short term follow-up, and large confidence intervals are the limitations of the current study. The Korean Hereditary Breast Cancer Study (KOHBRA Study) may definitely answer this question.

Controlling Linkage Disequilibrium in Association Tests: Revisiting APOE Association in Alzheimer's Disease

The allele frequencies of markers as well as linkage disequilibrium (LD) can be changed in cases due to the LD between markers and the disease allele, exhibiting spurious associations of markers. To identify the true association, classical statistical tests for dealing with confounders have been applied to draw a conclusion as to whether the association of variants comes from LD with the known disease allele. However, a more direct test considering LD using estimated haplotype frequencies may be more efficient. The null hypothesis is that the different allele frequencies of a variant between cases and controls come solely from the increased disease allele frequency and the LD relationship with the disease allele. The haplotype frequencies of controls are estimated using the expectation maximization (EM) algorithm from the genotype data. The estimated frequencies are applied to calculate the expected haplotype frequencies in cases corresponding to the increase or decrease of the causative or protective alleles. The suggested method was applied to previously published data, and several APOE variants showed association with Alzheimer's disease independent from the APOE epsilon4 variant, rs429358, regardless of LD showing significant simulated p-values. The test results support the possibility that there may be more than one common disease variant in a locus.

Epidemiology and genetics of hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a heart muscle disorder and is known to be inherited as an autosomal dominant trait. Mutations in several sarcomeric, cytoskeletal and mitochondrial genes have been reported in HCM. Though many cases of HCM are being identified, there is limited data regarding the epidemiology and genetics of HCM in India. Aim: Therefore the present study is envisaged at identifying the epidemiological variables in HCM and fitting a probability model assuming dominant mode of inheritance in HCM, which may in turn shed light on the heterogeneity of this complex disorder. Materials AND Methods: The 127 HCM cases were divided into subtypes based on pattern of hypertrophy. Chi square analysis, odds ratio, probability, relative frequency, penetrance and heritability estimates were calculated apart from epidemiological variables. Results: The HCM subtypes revealed the heterogeneous nature of the condition suggesting that the genes/mutations involved in their pathogenesis are different and this is supported by distinctive differences observed in their probability, heritability and penetrance estimates apart from epidemiological variables. An increased male preponderance was observed with the sex ratio being 3.7:1. The age at onset was found to be more than a decade early in familial cases (30 ± 10 yrs) compared to non familial cases (44 ± 14 yrs). Chi square analysis revealed obstructive HCM to be following autosomal dominant mode of inheritance where as non-obstructive HCM was significantly deviating. The level of deviation was significantly high for the middle onset group compared to early and late onset groups, therefore this group may be considered as an admixture wherein genes/gene modifiers and environmental variables may be contributing to the heterogeneity and this is further supported by odds ratio. Conclusions: The study thus brings out the complexity of HCM and suggests that modes of inheritance other than autosomal dominant may be encountered in a subset of HCM especially in asymmetric septal hypertrophy, apical, concentric and mid cavity obstruction subsets and hence a mixed model of inheritance is the best fit for such complex disorders.