Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.

Circ Arrhythm Electrophysiol. 2017 Apr;10(4):

Authors: Landstrom AP, Dailey-Schwartz AL, Rosenfeld JA, Yang Y, McLean MJ, Miyake CY, Valdes SO, Fan Y, Allen HD, Penny DJ, Kim JJ

Abstract
BACKGROUND: The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers.
METHODS AND RESULTS: CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world's largest collections of clinical WES referral tests (N=6517, Baylor Miraca Genetics Laboratories) and compared with a control cohort of ostensibly healthy individuals (N=60 706) and a case cohort of CPVT cases (N=155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicion for CPVT.
CONCLUSIONS: The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.

PMID: 28404607 [PubMed - in process]

Novel NLRC4 Mutation Causes a Syndrome of Perinatal Autoinflammation With Hemophagocytic Lymphohistiocytosis, Hepatosplenomegaly, Fetal Thrombotic Vasculopathy, and Congenital Anemia and Ascites.

Pediatr Dev Pathol. 2017 Jan 01;:1093526616686890

Authors: Liang J, Alfano DN, Squires JE, Riley MM, Parks WT, Kofler J, El-Gharbawy A, Madan-Kheterpal S, Acquaro R, Picarsic J

Abstract
Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of "secondary" HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.

PMID: 28403691 [PubMed - as supplied by publisher]

Baby genome screening needs more time to gestate.

Science. 2016 Oct 28;354(6311):398-399

Authors: Kaiser J

PMID: 27789817 [PubMed - indexed for MEDLINE]

Biotin-thiamine responsive basal ganglia disease: Identification of a pyruvate peak on brain spectroscopy, novel mutation in SLC19A3, and calculation of prevalence based on allele frequencies from aggregated next-generation sequencing data.

Am J Med Genet A. 2017 Apr 12;:

Authors: Ferreira CR, Whitehead MT, Leon E

Abstract
Biotin-thiamine responsive basal ganglia disease is an inborn error of metabolism caused by mutations in SLC19A3, encoding a transporter of thiamine across the plasma membrane. We report a novel mutation identified in the homozygous state in a patient with typical brain MRI changes. In addition, this patient had markedly elevated CSF pyruvate, a low lactate-to-pyruvate molar ratio, and an abnormal pyruvate peak at 2.4 ppm on brain magnetic resonance spectroscopy. Using aggregated exome sequencing data, we calculate the carrier frequency of mutations in SLC19A3 as 1 in 232 individuals in the general population, for an estimated prevalence of the disease of approximately 1 in 215,000 individuals. The disease is thus more frequent than previously recognized, and the presence of a pyruvate peak on spectroscopy could serve as an important diagnostic clue.

PMID: 28402605 [PubMed - as supplied by publisher]

LADD syndrome with glaucoma is caused by a novel gene.

Mol Vis. 2017;23:179-184

Authors: Simpson A, Avdic A, Roos BR, DeLuca A, Miller K, Schnieders MJ, Scheetz TE, Alward WL, Fingert JH

Abstract
PURPOSE: Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder displaying variable expression of multiple congenital anomalies including hypoplasia or aplasia of the lacrimal and salivary systems causing abnormal tearing and dry mouth. Mutations in the FGF10, FGFR2, and FGFR3 genes were found to cause some cases of LADD syndrome in prior genetic studies. The goal of this study is to identify the genetic basis of a case of LADD syndrome with glaucoma and thin central corneal thickness (CCT).
METHODS: Whole exome sequencing was performed, and previously described disease-causing genes (FGF10, FGFR2, and FGFR3) were first evaluated for mutations. Fifty-eight additional prioritized candidate genes were identified by searching gene annotations for features of LADD syndrome. The potential pathogenicity of the identified mutations was assessed by determining their frequency in large public exome databases; through sequence analysis using the Blosum62 matrix, PolyPhen2, and SIFT algorithms; and through homology analyses. A structural analysis of the effects of the top candidate mutation in tumor protein 63 (TP63) was also conducted by superimposing the mutation over the solved crystal structure.
RESULTS: No mutations were detected in FGF10, FGFR2, or FGFR3. The LADD syndrome patient's exome data was searched for mutations in the 58 candidate genes and only one mutation was detected, an Arg343Trp mutation in the tumor protein 63 (TP63) gene. This TP63 mutation is absent from the gnomAD sequence database. Analysis of the Arg343Trp mutation with Blosum62, PolyPhen2, and SIFT all suggest it is pathogenic. This arginine residue is highly conserved in orthologous genes. Finally, crystal structure analysis showed that the Arg343Trp mutation causes a significant alteration in the structure of TP63's DNA binding domain.
CONCLUSIONS: We report a patient with no mutations in known LADD syndrome genes (FGF10, FGFR2, and FGFR3). Our analysis provides strong evidence that the Arg343Trp mutation in TP63 caused LADD syndrome in our patient and that TP63 is a fourth gene contributing to this condition. TP63 encodes a transcription factor involved in the development and differentiation of tissues affected by LADD syndrome. These data suggest that TP63 is a novel LADD syndrome gene and may also influence corneal thickness and risk for open-angle glaucoma.

PMID: 28400699 [PubMed - in process]

Ethical considerations surrounding germline next generation sequencing of children with cancer.

Expert Rev Mol Diagn. 2017 Apr 12;:

Authors: Johnson LM, Hamilton KV, Valdez JM, Knapp E, Baker JN, Nichols KE

Abstract
INTRODUCTION: The advent of next generation sequencing (NGS) has introduced an exciting new era in biomedical research. NGS forms the foundation of current genetic testing approaches, including targeted gene panel testing, as well as more comprehensive whole exome and whole genome sequencing. Together, these approaches promise to provide critical insights into the understanding of health and disease. However, with NGS testing come many ethical questions and concerns, particularly when testing involves children. These concerns are especially relevant for children with cancer, where the testing of tumor and germline tissues is increasingly being incorporated into clinical care. Areas Covered: In this manuscript, the authors explore the key ethical considerations related to conducting germline NGS testing in pediatric oncology, focusing on the four main principles of beneficence, non-maleficence, autonomy and justice. Expert Commentary: The ethical issues surrounding germline NGS testing are complex and result in part from our limited understanding of the medical relevance of many of the results obtained and poor knowledge of the impacts of testing, both beneficial and detrimental, on patients and their families. The authors discuss the risks and benefits of germline NGS testing and the arguments for and against such testing in children with cancer.

PMID: 28399664 [PubMed - as supplied by publisher]

Sotos syndrome associated with Hirschsprung's disease: A new case and exome sequencing analysis.

Pediatr Res. 2017 Apr 11;:

Authors: Sio CA, Jung K, Kim JH, Cheong HS, Shin E, Jang H, Yoon M, Jang H, Shin HD

Abstract
BACKGROUND: Sotos syndrome (SoS) is an overgrowth disorder with various congenital anomalies and is usually accompanied by other clinical problems. However, anorectal malformations have not been documented as part of the SoS entity. Our objective is to report on a case of SoS associated with Hirschsprung's disease (HSCR) and subsequent genetic analysis.
METHODS: A 2 year old male with SoS experienced constipation since infancy and ultimately showed an aganglionic segment in the histopathologic examination and was followed by exome sequencing analysis.
RESULTS: In the genetic test for SoS diagnosis, two novel mutations of NDS1, c.2465C>A (p.Ser822Tyr) and c.4347T>A (p.Cys1449*), were observed and verified by re-sequencing in the patient and his parents. In further whole exome sequencing analysis using the patient's blood DNA, which was followed by a comparison analysis with the result of our previously reported genome-wide association study (GWAS) of HSCR, three genes (ZNF827, FGD2, and KCNJ12) with significance for HSCR from our previous GWAS were overlapped among the genes showing variants in the exome sequencing.
CONCLUSION: This is the first reported patient with SoS and HSCR. Further studies are required to determine whether there is a genetic relationship between SoS and HSCR.Pediatric Research accepted article preview online, 11 April 2017. doi:10.1038/pr.2017.106.

PMID: 28399120 [PubMed - as supplied by publisher]

Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development.

Sci Rep. 2017 Apr 11;7:46175

Authors: Ferre-Fernández JJ, Aroca-Aguilar JD, Medina-Trillo C, Bonet-Fernández JM, Méndez-Hernández CD, Morales-Fernández L, Corton M, Cabañero-Valera MJ, Gut M, Tonda R, Ayuso C, Coca-Prados M, García-Feijoo J, Escribano J

Abstract
Congenital glaucoma (CG) is a heterogeneous, inherited and severe optical neuropathy that originates from maldevelopment of the anterior segment of the eye. To identify new disease genes, we performed whole-exome sequencing of 26 unrelated CG patients. In one patient we identified two rare, recessive and hypermorphic coding variants in GPATCH3, a gene of unidentified function, and 5% of a second group of 170 unrelated CG patients carried rare variants in this gene. The recombinant GPATCH3 protein activated in vitro the proximal promoter of CXCR4, a gene involved in embryo neural crest cell migration. The GPATCH3 protein was detected in human tissues relevant to glaucoma (e.g., ciliary body). This gene was expressed in the dermis, skeletal muscles, periocular mesenchymal-like cells and corneal endothelium of early zebrafish embryos. Morpholino-mediated knockdown and transient overexpression of gpatch3 led to varying degrees of goniodysgenesis and ocular and craniofacial abnormalities, recapitulating some of the features of zebrafish embryos deficient in the glaucoma-related genes pitx2 and foxc1. In conclusion, our data suggest the existence of high genetic heterogeneity in CG and provide evidence for the role of GPATCH3 in this disease. We also show that GPATCH3 is a new gene involved in ocular and craniofacial development.

PMID: 28397860 [PubMed - in process]

Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

Mol Psychiatry. 2017 Apr 11;:

Authors: Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassinger C, Sheikh TI, Noor A, Mahmood H, Downey S, Johnson M, Vleuten K, Bell L, Ilyas M, Khan FS, Khan V, Moradi M, Ayaz M, Naeem F, Heidari A, Ahmed I, Ghadami S, Agha Z, Zeinali S, Qamar R, Mozhdehipanah H, John P, Mir A, Ansar M, French L, Ayub M, Vincent JB

Abstract
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.Molecular Psychiatry advance online publication, 11 April 2017; doi:10.1038/mp.2017.60.

PMID: 28397838 [PubMed - as supplied by publisher]

Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection.

Int J Legal Med. 2017 Apr 08;:

Authors: Gago-Díaz M, Ramos-Luis E, Zoppis S, Zorio E, Molina P, Braza-Boïls A, Giner J, Sobrino B, Amigo J, Blanco-Verea A, Carracedo Á, Brion M

Abstract
BACKGROUND: Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene​ assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.
MATERIALS AND METHODS: Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing.
RESULTS: From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.
CONCLUSIONS: This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.

PMID: 28391405 [PubMed - as supplied by publisher]

Identification of 2 Potentially Relevant Gene Mutations Involved in Strabismus Using Whole-Exome Sequencing.

Med Sci Monit. 2017 Apr 09;23:1719-1724

Authors: Min X, Fan H, Zhao G, Liu G

Abstract
BACKGROUND The etiology of strabismus has a genetic component. Our study aimed to localize the candidate causative gene mutant in a Chinese family with strabismus and to describe its underlying etiology. MATERIAL AND METHODS Genomic DNA was extracted from the affected individual and his parents in a Chinese pedigree with strabismus. The resulting exomes were sequenced by whole-exome sequencing. After variant calling and filtering, the candidate causative gene mutations were selected for the rarity and predicted damaging effect, which complied with the model of recessive disease transmission. RESULTS We examined a Chinese strabismus pedigree with the parents unaffected and 2 offspring affected. Whole-exome sequencing and bioinformatics filtering identified 2 variants including Abelson helper integration site 1 (AHI1) gene and nebulin (NEB) gene. The variant in the AHI1 gene, c.A3257G (p.E1086G), and the altered amino acid had a damaging effect on the encoded protein predicted by Polyphen2. Moreover, this change was located in the conserved SH3 domain of AHI1. Biallelic pathogenic variant in AHI1 gene can cause Joubert syndrome-related disorders with oculomotor apraxia characteristics. Additionally, c.A914G mutation was found in nebulin (NEB) gene. Therefore, we concluded that AHI1 c.3257A>G and NEB c.914 A>G were potential causal variants in this strabismus pedigree. CONCLUSIONS We detected an AHI1 homozygous mutation in the affected individual. Whole-exome sequencing is a powerful way to identify causally relevant genes, improving the understanding of this disorder.

PMID: 28391287 [PubMed - in process]

MYO15A splicing mutations in hearing loss: A review literature and report of a novel mutation.

Int J Pediatr Otorhinolaryngol. 2017 May;96:35-38

Authors: Motavaf M, Soveizi M, Maleki M, Mahdieh N

Abstract
Sensorineural hearing loss (SNHL) is the most prevalent genetic sensory defect in humans, affecting about 1 in 1000 newborns around the world. Non-syndromic SNHL accounts for nearly 70% of hereditary hearing loss and 80% of SNHL cases show an autosomal recessive mode of inheritance (ARNSHL). In the present study, we applied targeted-exome sequencing to a family with a single proband affected by congenital sensorineural hearing loss. 127 known genes were sequenced to find the causative mutation. One novel homozygous donor splice site mutation, c.4596 + 1G > A (IVS12 + 1G > A) was found in MYO15A gene. Analysis of this mutation within the family showed that the mutation segregates with hearing loss. New DNA sequencing technologies could lead to identification of the disease causing variants especially in highly heterogeneous disorders such as hearing loss.

PMID: 28390610 [PubMed - in process]

Myoepithelial carcinoma with RB1 mutation: remarkable chemosensitivity to carcinoma of unknown origin therapy.

BMC Cancer. 2017 Apr 08;17(1):250

Authors: Hoggard TM, Henderson-Jackson E, Bui MM, Caracciolo J, Teer JK, Yoder S, Binitie O, Gonzalez RJ, Brohl AS, Reed DR

Abstract
BACKGROUND: Myoepithelial carcinoma of soft tissue is a rare, malignant neoplasm that is morphologically and immunophenotypically similar to its counterpart in salivary gland. It demonstrates myoepithelial differentiation, possessing both epithelial and myogenic characteristics. Thought to be chemotherapy insensitive, the optimal treatment regimen of this tumor has yet to be established and only a select few cases in the literature discuss treatment efficacy in detail.
CASE PRESENTATION: Here we present a case of a young adult with metastatic myoepithelial carcinoma with an initial excellent response to systemic therapy utilizing carboplatin and paclitaxel with continued complete response after 3 years. The patient also underwent complete surgical excision and received adjuvant radiation to the primary site of disease. Exome sequencing revealed an inactivating mutation in RB1 which we believe to be the first such mutation to be reported in this cancer type.
CONCLUSIONS: Given increasing evidence suggesting RB1 loss is associated with responsiveness to conventional chemotherapies, particularly platinum-based regimens, we hypothesize that this genetic feature predisposed chemosensitivity in our patient's tumor.

PMID: 28390395 [PubMed - in process]

Familial Early-Onset Paget's Disease of Bone Associated with a Novel hnRNPA2B1 Mutation.

Calcif Tissue Int. 2017 Apr 07;:

Authors: Qi X, Pang Q, Wang J, Zhao Z, Wang O, Xu L, Mao J, Jiang Y, Li M, Xing X, Yu W, Asan, Xia W

Abstract
Paget disease of bone (PDB) is a common metabolic bone disease characterized by increased bone resorption and disorganized bone formation which affect single or multiple sites of bones. Although the exact cause of PDB is still controversial, genetic factors are considered to play an important role in PDB. Several genes involved in the differentiation or function of osteoclast were shown to be associated with PDB or related syndrome such as SQSTM1, TNFRSF11A, TNFRSF11B, and ZNF687. Multisystem proteinopathy (MSP), a newly proposed syndrome including inclusion body myopathy (IBM), PDB, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), is mainly caused by mutation in VCP gene. In 2013, a new casual gene for MSP was identified as hnRNPA2B1 gene. This may partly account for the inherited PDB traits which is however negative for mutation in already known causative PDB genes. We investigated a Chinese family with multiple affected individuals with PDB, but none of the members showed symptoms of IBM, FTD, or ALS. Three patients were evaluated clinically, biochemically, and radiographically. To screen for the responsible mutation, whole-exome sequencing was conducted in the proband, another patient, as well as a normal individual from the family. This revealed a novel heterozygous missense mutation of hnRNPA2B1 gene (c.929C>T, p. P310L) in the two patients which was then verified in all affected individuals. We describe here a novel missense mutation in hnRNPA2B1 gene in a large pedigree affected with PDB with members who do not present other manifestations of multisystem proteinopathy, such as IBM, FTD, and ALS.

PMID: 28389692 [PubMed - as supplied by publisher]

Large Scale Analysis of Variation in the Insulin-like Growth Factor Family in Humans Reveals Rare Disease Links and Common Polymorphisms.

J Biol Chem. 2017 Apr 07;:

Authors: Rotwein P

Abstract
The insulin-like growth factors IGF1 and IGF2 are closely related proteins that are essential for normal growth and development in humans and other species and play critical roles in many physiological and patho-physiological processes. IGF actions are mediated by trans-membrane receptors and modulated by IGF binding proteins. The importance of IGF actions in human physiology is strengthened by the rarity of inactivating mutations in their genes, and by the devastating impact caused by such mutations on normal development and somatic growth. Large-scale genome sequencing has the potential to provide new insights into human variation and disease susceptibility. Toward this end the availability of DNA sequence data from 60,706 people through the Exome Aggregation Consortium has prompted the analyses presented here. Results reveal a broad range of potential missense and other alterations in the coding regions of every IGF family gene but the vast majority of predicted changes were uncommon. The total number of different alleles detected per gene in the population varied over an ~15-fold range, from 57 for IGF1 to 872 for IGF2R, although when corrected for protein length, the rate ranged from 0.22 to 0.59 changes/codon among the 11 genes evaluated. Previously characterized disease-causing mutations in IGF2, IGF1R, IGF2R, or IGFALS all were found in the general population, but with allele frequencies of < 1:30,000. A few new highly prevalent amino acid polymorphisms also were identified. Collectively, these data provide a wealth of opportunities to understand the intricacies of IGF signaling and action in both physiological and pathological contexts.

PMID: 28389567 [PubMed - as supplied by publisher]

A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension.

BMC Pulm Med. 2017 Apr 07;17(1):57

Authors: Higasa K, Ogawa A, Terao C, Shimizu M, Kosugi S, Yamada R, Date H, Matsubara H, Matsuda F

Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe lung disease with only few effective treatments available. Familial cases of PAH are usually recognized as an autosomal dominant disease, but incomplete penetrance of the disease makes it difficult to identify pathogenic variants in accordance with a Mendelian pattern of inheritance.
METHODS: To elucidate the complex genetic basis of PAH, we obtained whole exome- or genome-sequencing data of 17 subjects from 9 families with heritable PAH and applied gene-based association analysis with 9 index patients and 300 PAH-free controls.
RESULTS: A burden of rare variants in BMPR2 significantly contributed to the risk of the disease (p = 6.0 × 10(-8)). Eight of nine families carried four previously reported single nucleotide variants and four novel insertion/deletion variants in the gene. One of the novel variants was a large 6.5 kilobase-deletion. In the remaining one family, the patient carried a pathogenic variant in a member of potassium channels, KCNK3, which was the first replicative finding of channelopathy in an Asian population.
CONCLUSIONS: The variety of rare pathogenic variants suggests that gene-based association analysis using genome-wide sequencing data from increased number of samples is essential to tracing the genetic heterogeneity and developing an appropriate panel for genetic testing.

PMID: 28388887 [PubMed - in process]

A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations.

Clin Genet. 2017 Apr 06;:

Authors: Ritelli M, Morlino S, Giacopuzzi E, Bernardini L, Torres B, Santoro G, Ravasio V, Chiarelli N, D'Angelantonio D, Novelli A, Grammatico P, Colombi M, Castori M

Abstract
Deletions encompassing TAK1-binding protein 2 (TAB2) associate with isolated and syndromic congenital heart defects. Rare missense variants are found in patients with a similar phenotype as well as in a single individual with frontometaphyseal dysplasia. We describe a family and an additional sporadic patient with polyvalvular heart disease, generalized joint hypermobility and related musculoskeletal complications, soft, velvety and hyperextensible skin, short limbs, hearing impairment, and facial dysmorphism. In the first family, whole exome sequencing disclosed the novel TAB2 c.1398dup (p.Thr467Tyrfs*6) variant that eliminates the C-terminal zinc finger domain essential for activation of TAK1 (TGFβ-activated kinase 1)-dependent signaling pathways. The sporadic case carryed a ~2 Mb de novo deletion including 28 genes also comprising TAB2. This study reveal an association between TAB2 mutations and a phenotype resembling Ehlers-Danlos syndrome with severe polyvalvular heart disease and subtle facial dysmorphism. Our findings support the existence of a wider spectrum of clinical phenotypes associated with TAB2 perturbations and emphasize the role of TAK1 signaling network in human development.

PMID: 28386937 [PubMed - as supplied by publisher]

Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.

Hum Genet. 2017 Apr 06;:

Authors: Renkema GH, Visser G, Baertling F, Wintjes LT, Wolters VM, van Montfrans J, de Kort GA, Nikkels PG, van Hasselt PM, van der Crabben SN, Rodenburg RJ

Abstract
The genetic basis of the many progressive, multi systemic, mitochondrial diseases that cause a lack of cellular ATP production is heterogeneous, with defects found both in the mitochondrial genome as well as in the nuclear genome. Many different mutations have been found in the genes encoding subunits of the enzyme complexes of the oxidative phosphorylation system. In addition, mutations in genes encoding proteins involved in the assembly of these complexes are known to cause mitochondrial disorders. Here we describe two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits. Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor. PET117 has not been identified as a mitochondrial disease gene before. Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients, and indicating a pivotal role of this protein in the proper functioning of complex IV. Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this. This case presentation thus implicates mutations in PET117 as a novel cause of mitochondrial disease.

PMID: 28386624 [PubMed - as supplied by publisher]

Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation.

J Dermatol Sci. 2017 Mar 27;:

Authors: Molho-Pessach V, Ramot Y, Mogilevsky M, Cohen-Daniel L, Eisenstein EM, Abu-Libdeh A, Siam I, Berger M, Karni R, Zlotogorski A

Abstract
BACKGROUND: Generalized verrucosis (GV) is a chronic and progressive cutaneous human papillomavirus (HPV) infection resulting in multiple warts and associated with acquired or genetic immune defects. We identified a consanguineous Arab family manifesting GV and recurrent bacterial and viral infections, in association with inflammatory bowel disease (IBD).
OBJECTIVE: To identify the mutated gene responsible for GV, recurrent infections and IBD, in this family.
METHODS: Flow cytometry of peripheral blood mononuclear cells was performed, as well as proliferation and cell cycle assays of T cells. Whole exome sequencing was utilized to detect candidate mutated genes, assuming an autosomal recessive mode of inheritance. Skin fibroblasts from a patient, the mother and control were incubated with sorbitol to detect the phosphorylation ability of TAOK2, and a clonogenic assay was performed to assess the survival and proliferative capacity of fibroblasts' colonies.
RESULTS: Despite normal immunophenotyping of T and B cells, T cell proliferation upon activation was impaired in a patient compared to a heterozygous family member and a control. Genetic analyses identified a rare homozygous missense variant, c.2098C>T (p.R700C) in the TAOK2 gene, segregating with the disease phenotype in the family. TAOK2 encodes the TAO2 kinase, a mitogen activated protein kinase kinase kinase (MAP3K) in the p38-MAPK cascade. The mutation is predicted to disrupt its normal folding and molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts. Despite this normal kinase activity, a noticeably higher survival/proliferation of patient's skin fibroblasts was found.
CONCLUSIONS: A mutation in TAOK2 appears to cause a novel form of primary immunodeficiency, characterized by an impaired T cell proliferation upon activation. This novel cause of GV gives further support to the importance of the p38-MAPK pathway in the immune response against HPV, and possibly also in the pathogenesis of IBD.

PMID: 28385331 [PubMed - as supplied by publisher]

Exome Sequence Analysis of 14 Families With High Myopia.

Invest Ophthalmol Vis Sci. 2017 Apr 01;58(4):1982-1990

Authors: Kloss BA, Tompson SW, Whisenhunt KN, Quow KL, Huang SJ, Pavelec DM, Rosenberg T, Young TL

Abstract
Purpose: To identify causal gene mutations in 14 families with autosomal dominant (AD) high myopia using exome sequencing.
Methods: Select individuals from 14 large Caucasian families with high myopia were exome sequenced. Gene variants were filtered to identify potential pathogenic changes. Sanger sequencing was used to confirm variants in original DNA, and to test for disease cosegregation in additional family members. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were comprehensively screened.
Results: In 14 high myopia families, we identified 73 rare and 31 novel gene variants as candidates for pathogenicity. In seven of these families, two of the novel and eight of the rare variants were within known myopia loci. A total of 104 heterozygous nonsynonymous rare variants in 104 genes were identified in 10 out of 14 probands. Each variant cosegregated with affection status. No rare variants were identified in genes known to cause myopia or in genes closest to published genome-wide association study association signals for refractive error or its endophenotypes.
Conclusions: Whole exome sequencing was performed to determine gene variants implicated in the pathogenesis of AD high myopia. This study provides new genes for consideration in the pathogenesis of high myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.

PMID: 28384719 [PubMed - in process]