Objective

We report a 35 year-old male with childhood learning disability and early onset dementia who is homozygous for the A431E variant in the PSEN1 gene. Presenilin1 mutations are associated with autosomal dominant Alzheimer's dementia with young and somewhat stereotyped onset. Such variants may cause Alzheimer's dementia through aberrant processing of amyloid precursor protein through effects on γ-secretase activity. γ-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin1 function is of interest.

Methods

Clinical evaluation including family history, examination, brain MRI, and genetic analysis.

Results

Our patient had mild developmental delay, chronic nighttime behavioral disturbance, and onset of progressive cognitive deficits at age 33. Clinical evaluation demonstrated spastic paraparesis and pseudobulbar affect. Brain MRI revealed cerebral atrophy disproportionate to age. Chronic microhemorrhages within bilateral occipital, temporal, and right frontal lobes were seen. Sanger sequencing confirmed homozygosity for the A431E variant in PSEN1, which is a known pathogenic variant causing autosomal dominant Alzheimer's dementia.

Conclusions

Our report demonstrates that homozygosity for pathogenic Presenilin1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.

DNA mismatch-repair gene mutations, with consequent loss of functional protein expression, result in microsatellite instability (MSI). Microsatellite sequences are found in coding regions and in regulatory regions of genes (i.e., 5'-UTRs and 3'-UTRs). In addition to being a surrogate marker of defective mismatch repair, deletion or insertion microsatellite sequences can dysregulate gene expression in MSI-H (microsatellite instability-high) tumors. The microsomal prostaglandin E synthase-1 (mPGES-1) gene product, mPGES-1, participates in prostaglandin E2 (PGE2) production. Moreover, mPGES-1 is often overexpressed in human colorectal tumors, and is thought to contribute to progression of these tumors. Here we identified a dinucleotide repeat, (GT)24, in the mPGES-1 gene 3' untranslated region (3'-UTR), and analyzed its mutation frequencies in MSI-H and microsatellite stable (MSS) tumors. The (GT)24 repeat exhibited instability in all MSI-H tumors examined (14), but not in any of the MSS tumors (13). In most cases, (GT)24 repeat instability resulted in insertion of additional GT units. We also determined mPGES-1 mRNA levels in MSI-H and MSS colorectal cancer cell lines. Three of four previously designated "MSI-H" cell lines showed higher mPGES-1 mRNA levels compared to MSS cell lines; correlations between elevated mPGES-1 mRNA levels and microsatellite (GT)24 repeat characteristics are present for all six cell lines. Our results demonstrate that mPGES-1 is a target gene of defective mismatch repair in human colorectal cancer, with functional consequence.

PURPOSE: Sanger sequencing is currently considered the gold standard methodology for clinical molecular diagnostic testing. However, next-generation sequencing has already emerged as a much more efficient means to identify genetic variants within gene panels, the exome, or the genome. We sought to assess the accuracy of next-generation sequencing variant identification in our clinical genomics laboratory with the goal of establishing a quality score threshold for confirmatory Sanger-based testing. METHODS: Confirmation data for reported results from 144 sequential clinical exome-sequencing cases (94 unique variants) and an additional set of 16 variants from comparable research samples were analyzed. RESULTS: Of the 110 total single-nucleotide variants analyzed, 103 variants had a quality score ≥Q500, 103 (100%) of which were confirmed by Sanger sequencing. Of the remaining seven variants with quality scores

A term male neonate developed severe intractable lactic acidosis on day of life 1 and died the same day at our institution. The family previously lost another term, female newborn on day of life 1 from suspected sepsis at an outside hospital. After performing an autopsy on the neonate who died at our institution, extensive and lengthy neonatal and parental genetic testing, as well as biochemical analyses, and whole exome sequencing analysis identified compound heterozygous mutations in the lipoyltransferase 1 (LIPT1) gene responsible for the lipoylation of the 2-keto dehydrogenase complexes in the proband. These mutations were also identified in the deceased sibling. The clinical manifestations of these two siblings are consistent with those recently described in two unrelated families with lactic acidosis due to LIPT1 mutations, an underrecognized and underreported cause of neonatal death. Conclusions. Our observations contribute to the delineation of a new autosomal recessive metabolic disorder, leading to neonatal death. Our case report also highlights the importance of an interdisciplinary team in solving challenging cases.

Objective

We report a 35 year-old male with childhood learning disability and early onset dementia who is homozygous for the A431E variant in the PSEN1 gene. Presenilin1 mutations are associated with autosomal dominant Alzheimer's dementia with young and somewhat stereotyped onset. Such variants may cause Alzheimer's dementia through aberrant processing of amyloid precursor protein through effects on γ-secretase activity. γ-secretase is involved in the cleavage of many proteins critical to normal function, including brain development. Therefore, manifestations in persons without normal Presenilin1 function is of interest.

Methods

Clinical evaluation including family history, examination, brain MRI, and genetic analysis.

Results

Our patient had mild developmental delay, chronic nighttime behavioral disturbance, and onset of progressive cognitive deficits at age 33. Clinical evaluation demonstrated spastic paraparesis and pseudobulbar affect. Brain MRI revealed cerebral atrophy disproportionate to age. Chronic microhemorrhages within bilateral occipital, temporal, and right frontal lobes were seen. Sanger sequencing confirmed homozygosity for the A431E variant in PSEN1, which is a known pathogenic variant causing autosomal dominant Alzheimer's dementia.

Conclusions

Our report demonstrates that homozygosity for pathogenic Presenilin1 variants is compatible with life, though may cause a more aggressive phenotype with younger age of onset and possibly REM behavior disorder.

Limited data suggest that enhanced self-knowledge from genetic information related to non-medical traits can have a positive impact on psychological well-being. Deaf individuals undertake genetic testing for deaf genes to increase self-knowledge. Because deafness is considered a non-medical trait by many individuals, we hypothesized that deaf individuals receiving a genetic explanation for why they are deaf will experience increased psychological well-being. We report results from a prospective, longitudinal study to determine the impact of genetic testing (GJB2, Cx26; GJB6, Cx30) on perceived personal control (PPC), anxiety, and depression in deaf adults (N = 209) assessed following pre-test genetic counseling as well as 1-month and 6-months following test result disclosure. Participants were classified as Cx positive (n = 82) or Cx negative/inconclusive (n = 127). There was significant evidence for Cx group differences in PPC and anxiety over time (PPC: Cx group*time interaction p = 0.0007; anxiety: Cx group*time interaction p = 0.002), where PPC scores were significantly higher, and anxiety scores were significantly lower for the Cx positive group relative to the negative/inconclusive group following test result disclosure. Compared to pre-test, PPC scores increased at 1-month (p = 0.07) and anxiety scores decreased at 6-months (p = 0.03) for the Cx positive group. In contrast, PPC scores decreased (p = 0.009, p < 0.0001) and anxiety scores increased (p = 0.09, p = 0.02) for the Cx negative/inconclusive group at 1- and 6-months post test result disclosure. Genetic testing for deaf genes affects the psychological well-being of deaf individuals. Increasing deaf adults' access to genetic testing may potentially enhance self-knowledge and increase psychological well-being for those who receive a genetic explanation, which could offer downstream health benefits.

Background

Wiedemann-Steiner Syndrome (WSS) is characterized by short stature, a variety of dysmorphic facial and skeletal features, characteristic hypertrichosis cubiti (excessive hair on the elbows), mild-to-moderate developmental delay and intellectual disability. [MIM#: 605130]. Here we report two unrelated children for whom clinical exome sequencing of parent-proband trios was performed at UCLA, resulting in a molecular diagnosis of WSS and atypical clinical presentation.

Case presentation

For patient 1, clinical features at 9 years of age included developmental delay, craniofacial abnormalities, and multiple minor anomalies. Patient 2 presented at 1 year of age with developmental delay, microphthalmia, partial 3-4 left hand syndactyly, and craniofacial abnormalities. A de novo missense c.4342T>C variant and a de novo splice site c.4086+G>A variant were identified in the KMT2A gene in patients 1 and 2, respectively.

Conclusions

Based on the clinical and molecular findings, both patients appear to have novel presentations of WSS. As the hallmark hypertrichosis cubiti was not initially appreciated in either case, this syndrome was not suspected during the clinical evaluation. This report expands the phenotypic spectrum of the clinical phenotypes and KMT2A variants associated with WSS.

Importance

Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.

Objective

To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.

Design, setting, and participants

We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.

Main outcomes and measures

Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.

Results

We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.

Conclusions and relevance

This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.

Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aortic lesions from liver and adipose tissues of these mice, and we experimentally validated one of these candidate causal genes, complement component 3a receptor 1 (C3ar1), using a knockout mouse model. We also found that genes identified by this method overlapped with genes progressively regulated in the aortic arches of 2 mouse models of atherosclerosis during atherosclerotic lesion development. By comparing our gene set with findings from public human genome-wide association studies (GWAS) of CAD and related traits, we found that 5 genes identified by our study overlapped with published studies in humans in which they were identified as risk factors for multiple atherosclerosis-related pathologies, including myocardial infarction, serum uric acid levels, mean platelet volume, aortic root size, and heart failure. Candidate causal genes were also found to be enriched with CAD risk polymorphisms identified by the Wellcome Trust Case Control Consortium (WTCCC). Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development.