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Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation.

ABSTRACT: We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD.

SUBMITTER: Bras J

PROVIDER: S-EPMC5166571 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation.

Bras Jose J Djaldetti Ruth R Alves Ana Margarida AM Mead Simon S Darwent Lee L Lleo Alberto A Molinuevo Jose Luis JL Blesa Rafael R Singleton Andrew A Hardy John J Clarimon Jordi J Guerreiro Rita R

Neurobiology of aging 20160704

We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: th ...[more]

PMID: 27524508

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Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia.

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Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.

Project description:Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.

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Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome.

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Project description: Not available

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Exome sequencing analysis identifies novel homozygous mutation in ABCA4 in a Chinese family with Stargardt disease.

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| S-EPMC7137712 | biostudies-literature

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Project description:BACKGROUND: Usher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family. METHODS: Candidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing. RESULTS: Using a capture array targeting the three identified homozygosity-by-descent regions on chromosomes 1q43-q44, 20p13-p12.2 and 20p11.23-q12, we identified a homozygous nonsense mutation, p.Arg65X, in ABHD12 segregating with the phenotype. CONCLUSION: Mutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract). After the identification of the ABHD12 mutation in this family, one patient underwent neurological examination which revealed ataxia, but no polyneuropathy. ABHD12 is not known to be related to the USH protein interactome. The phenotype of our patient represents a variant of PHARC, an entity that should be taken into account as differential diagnosis for USH3. Our study demonstrates the potential of comprehensive genetic analysis for improving the clinical diagnosis.

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Adult-onset Krabbe disease due to a homozygous GALC mutation without abnormal signals on an MRI in a consanguineous family: A case report.

Project description:BackgroundThe most frequent and common form of Krabbe disease (KD) is early-onset KD in infants, and late-onset KD has been reported to be a rare disease. In the present study, we reported an adult-onset KD patient in a consanguineous Chinese family.MethodsClinical and radiological data were collected for a family pedigree. The patient was diagnosed with late-onset KD through next-generation sequencing. The result was confirmed by Sanger sequencing. GALC enzyme activity was also examined by the colorimetry method. Both the grey matter volume (GMV) and white matter volume values were examined and compared with the average values from ten age-matched normal controls. Moreover, we reviewed all the available KD studies on PubMed to understand the correlation between the phenotype and genotype of the identified mutation.ResultsThe main manifestations of the proband were sudden onset seizures and cognitive decline. Mutation analysis of the GALC revealed a homozygous c.1901T>C mutation in exon 16, which resulted in an amino acid change in p.L634S. Sanger sequencing results showed that the homozygous mutation was inherited from the patient's parents, both of whom were revealed to be heterozygous carriers. Moreover, a decrease in GALC enzyme activity was also detected. However, no abnormal signals were found in the brain MRI. Further structural MRI analysis revealed a significantly decreased GMV in the proband compared to the normal controls. Moreover, it is of interest that all patients with the c.1901T>C mutation had late-onset KD and were selected from Asian countries, especially Japan and China.ConclusionsThis patient with a homozygous GALC mutation expands the clinical presentation and characteristics of adult-onset KD, as indicated by grey matter atrophy without abnormal white matter signals.

| S-EPMC7507702 | biostudies-literature

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer's Disease.

Project description:Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer's disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders' genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.

| S-EPMC6471359 | biostudies-literature

Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family.

Project description:PurposeVariations in many genes may lead to the occurrence of oocyte maturation defects. To investigate the genetic basis of oocyte maturation defects, we performed clinical and genetic analysis of a pedigree.MethodsThe proband with oocyte maturation defect-2 receiving ovulation induction therapy and her parents were selected for clinical detection, whole exome sequencing and Sanger sequencing. One unrelated healthy woman received ovulation induction therapy as control. Mutations were assessed after frequency screening of public exome databases. Then homozygous variants shared by the proband and her parents were selected.ResultsArrest of oocytes maturation was observed. A new missense mutation in TUBB8 (TUBB8: NM_177,987: exon 2: c. C161T: p. A54V) was identified, which was shown to be rare compared with public databases. The variant was highly conserved among primates, and was suggested to be deleterious by online software prediction.ConclusionsThe homozygote of this variant (TUBB8: NM_ 177,987: exon 2:c.C161T: p.A54V) might affect spindle assembly, cause arrest of oocyte maturation and lead to oocyte maturation defect-2.

| S-EPMC7175565 | biostudies-literature

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