Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy ...7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scores possible, one of which was in a commonly microdeleted chromosome 7q region. Exome sequencing identified a missense mutation (c.2640C>A, p.His880Gln) in the sterile alpha motif domain containing 9-like gene (SAMD9L) that completely cosegregated with disease. By targeted sequencing of SAMD9L, we subsequently identified a different missense mutation (c.3587G>C, p.Cys1196Ser) in affected members of the first described family with AP syndrome, Li-AP. Neither variant is reported in the public databases, both affect highly conserved amino acid residues, and both are predicted to be damaging. With time in culture, lymphoblastic cell lines (LCLs) from two affected individuals in family UW-AP exhibited copy-neutral loss of heterozygosity for large portions of the long arm of chromosome 7, resulting in retention of only the wild-type SAMD9L allele. Newly established LCLs from both individuals demonstrated the same phenomenon. In addition, targeted capture and sequencing of SAMD9L in uncultured blood DNA from both individuals showed bias toward the wild-type allele. These observations indicate in vivo hematopoietic mosaicism. The hematopoietic cytopenias that characterize AP syndrome and the selective advantage for clones that have lost the mutant allele support the postulated role of SAMD9L in the regulation of cell proliferation. Furthermore, we show that AP syndrome is distinct from the dyskeratoses congenita telomeropathies, with which it shares some clinical characteristics.
Understanding and correctly utilizing relatedness among samples is essential for genetic analysis; however, managing sample records and pedigrees can often be error prone and incomplete. Data sets ...ascertained by random sampling often harbor cryptic relatedness that can be leveraged in genetic analyses for maximizing power. We have developed a method that uses genome-wide estimates of pairwise identity by descent to identify families and quickly reconstruct and score all possible pedigrees that fit the genetic data by using up to third-degree relatives, and we have included it in the software package PRIMUS (Pedigree Reconstruction and Identification of the Maximally Unrelated Set). Here, we validate its performance on simulated, clinical, and HapMap pedigrees. Among these samples, we demonstrate that PRIMUS can verify reported pedigree structures and identify cryptic relationships. Finally, we show that PRIMUS reconstructed pedigrees, all of which were previously unknown, for 203 families from a cohort collected in Starr County, TX (1,890 samples).
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing ...factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.
Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole‐exome sequencing (WES) has increased the overall diagnostic ...rate considerably. However, the upper limit of this method remains ill‐defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic‐onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES‐based methods and a more comprehensive genome‐wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. To assess rare coding variation in ataxic disorders, we performed whole‐exome sequencing of patients (n = 260) including analysis for copy number variation and repeat expansion in a representative subset. We suggest that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES‐based methods and a more comprehensive genome‐wide assessment is needed to further improve diagnosis.
Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is ...heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in
TSPEAR
, associated with syndromic and isolated TA in one family each; a variant in
LAMB3
associated with syndromic TA in one family; and a variant in
BCOR
plus a disease-associated
WNT10A
variant in one family with syndromic TA. With the notable exception of
WNT10A
(Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes:
TSPEAR
(Deafness, autosomal recessive 98, MIM #614861),
LAMB3
(Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and
BCOR
(Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose
TSPEAR
as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the
BCOR
and
WNT10A
loci, underscoring the complexity of the genotype–phenotype relationship in the common complex trait of TA.
Mexican Americans are disproportionally affected by non-alcoholic fatty liver disease (NAFLD), liver fibrosis and hepatocellular carcinoma. Noninvasive means to identify those in this population at ...high risk for these diseases are urgently needed.
The Cameron County Hispanic Cohort (CCHC) is a population-based cohort with high rates of obesity (51%), type 2 diabetes (28%) and NAFLD (49%). In a subgroup of 564 CCHC subjects, we evaluated 339 genetic variants previously reported to be associated with liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in United Kingdom and Japanese cohorts.
Association was confirmed for 86 variants. Among them, 27 had higher effect allele frequency in the CCHC than in the United Kingdom and Japanese cohorts, and 16 had stronger associations with AST and ALT than rs738409 (
). These included rs17710008 (
)
rs2519093 (
), rs1801690 (
), rs10409243 (
), rs1800759 (
) and rs2491441 (
)
which were also associated with steatosis and/or liver fibrosis measured by vibration-controlled transient elastography. Main contributors to advanced fibrosis risk were rs11240351 (
), rs1800759 (
)
rs738409 (
) and rs1801690 (
), with advanced fibrosis detected in 37.5% of subjects with 3 of these 4 variants AOR = 11.6 (95% CI) = 3.8-35.3. AST- and ALT-associated variants implicated distinct pathways (ethanol and galactose degradation
antigen presentation and B cell development). Finally, 8 variants, including rs62292950 (
), were associated with gut microbiome changes.
These genotype-phenotype findings may have utility in risk modeling and disease prevention in this high-risk population.
Statistical analyses are a crucial component of the biomedical research process and are necessary to draw inferences from biomedical research data. The application of sound statistical methodology is ...a prerequisite for publication in the American Heart Association (AHA) journal portfolio. The objective of this document is to summarize key aspects of statistical reporting that might be most relevant to the authors, reviewers, and readership of AHA journals. The AHA Scientific Publication Committee convened a task force to inventory existing statistical standards for publication in biomedical journals and to identify approaches suitable for the AHA journal portfolio. The experts on the task force were selected by the AHA Scientific Publication Committee, who identified 12 key topics that serve as the section headers for this document. For each topic, the members of the writing group identified relevant references and evaluated them as a resource to make the standards summarized herein. Each section was independently reviewed by an expert reviewer who was not part of the task force. Expert reviewers were also permitted to comment on other sections if they chose. Differences of opinion were adjudicated by consensus. The standards presented in this report are intended to serve as a guide for high-quality reporting of statistical analyses methods and results.
We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led ...to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with β cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially β cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of β cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.
Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ∼50% of cases are caused by mutations in genes that encode contractile proteins of ...skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ∼70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.
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