Leveraging multiple genomic data to prioritize disease-causing indels from exome sequencing data.

Sci Rep. 2017 May 11;7(1):1804

Authors: Wu M, Chen T, Jiang R

Abstract
The emergence of exome sequencing in recent years has enabled rapid and cost-effective detection of genetic variants in coding regions and offers a great opportunity to combine sequencing experiments with subsequent computational analysis for dissecting genetic basis of human inherited diseases. However, this strategy, though successful in practice, still faces such challenges as limited sample size and substantial number or diversity of candidate variants. To overcome these obstacles, researchers have been concentrated in the development of advanced computational methods and have recently achieved great progress for analysing single nucleotide variant. Nevertheless, it still remains unclear on how to analyse indels, another type of genetic variant that accounts for substantial proportion of known disease-causing variants. In this paper, we proposed an integrative method to effectively identify disease-causing indels from exome sequencing data. Specifically, we put forward a statistical method to combine five functional prediction scores, four genic association scores and a genic intolerance score to produce an integrated p-value, which could then be used for prioritizing candidate indels. We performed extensive simulation studies and demonstrated that our method achieved high accuracy in uncovering disease-causing indels. Our software is available at http://bioinfo.au.tsinghua.edu.cn/jianglab/IndelPrioritizer/.

PMID: 28496131 [PubMed - in process]

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Eur Respir J. 2017 May;49(5):

Authors: Juge PA, Borie R, Kannengiesser C, Gazal S, Revy P, Wemeau-Stervinou L, Debray MP, Ottaviani S, Marchand-Adam S, Nathan N, Thabut G, Richez C, Nunes H, Callebaut I, Justet A, Leulliot N, Bonnefond A, Salgado D, Richette P, Desvignes JP, Lioté H, Froguel P, Allanore Y, Sand O, Dromer C, Flipo RM, Clément A, Béroud C, Sibilia J, Coustet B, Cottin V, Boissier MC, Wallaert B, Schaeverbeke T, Dastot le Moal F, Frazier A, Ménard C, Soubrier M, Saidenberg N, Valeyre D, Amselem S, FREX consortium, Boileau C, Crestani B, Dieudé P

Abstract
Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10(-4)). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10(-2)).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

PMID: 28495692 [PubMed - in process]

Establishing a patient-derived xenograft model of human myxoid and round-cell liposarcoma.

Oncotarget. 2017 Apr 21;:

Authors: Qi Y, Hu Y, Yang H, Zhuang R, Hou Y, Tong H, Feng Y, Huang Y, Jiang Q, Ji Q, Gu Q, Zhang Z, Tang X, Lu W, Zhou Y

Abstract
Myxoid and round cell liposarcoma (MRCL) is a common type of soft tissue sarcoma. The lack of patient-derived tumor xenograft models that are highly consistent with human tumors has limited the drug experiments for this disease. Hence, we aimed to develop and validate a patient-derived tumor xenograft model of MRCL. A tumor sample from a patient with MRCL was implanted subcutaneously in an immunodeficient mouse shortly after resection to establish a patient-derived tumor xenograft model. After the tumor grew, it was resected and divided into several pieces for re-implantation and tumor passage. After passage 1, 3, and 5 (i.e. P1, P3, and P5, respectively), tumor morphology and the presence of the FUS-DDIT3 gene fusion were consistent with those of the original patient tumor. Short tandem repeat analysis demonstrated consistency from P1 to P5. Whole exome sequencing also showed that P5 tumors harbored many of the same gene mutations present in the original patient tumor, one of which was a PIK3CA mutation. PF-04691502 significantly inhibited tumor growth in P5 models (tumor volumes of 492.62 ± 652.80 vs 3303.81 ± 1480.79 mm3, P < 0.001, in treated vs control tumors, respectively) after 29 days of treatment. In conclusion, we have successfully established the first patient-derived xenograft model of MRCL. In addition to surgery, PI3K/mTOR inhibitors could potentially be used for the treatment of PIK3CA-positive MRCLs.

PMID: 28493834 [PubMed - as supplied by publisher]

Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy.

Hum Mutat. 2017 May 11;:

Authors: Nakayama T, Wu J, Galvin-Parton P, Weiss J, Andriola MR, Hill RS, Vaughan D, El-Quessny M, Barry BJ, Partlow JN, Barkovich AJ, Ling J, Mochida GH

Abstract
Aminoacyl-transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl-tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot-Marie-Tooth (CMT) disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here we report loss-of-function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy and spasticity. Whole exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70-90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS-related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity. This article is protected by copyright. All rights reserved.

PMID: 28493438 [PubMed - as supplied by publisher]

Common Variable Immunodeficiency Caused by FANC Mutations.

J Clin Immunol. 2017 May 11;:

Authors: Sekinaka Y, Mitsuiki N, Imai K, Yabe M, Yabe H, Mitsui-Sekinaka K, Honma K, Takagi M, Arai A, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Muramatsu H, Kojima S, Hira A, Takata M, Ohara O, Ogawa S, Morio T, Nonoyama S

Abstract
Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4(+) T cells were skewed toward CD45RO(+) memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.

PMID: 28493158 [PubMed - as supplied by publisher]

Hypomyelinating leukodystrophy associated with a deleterious mutation in the ATRN gene.

Neurogenetics. 2017 May 10;:

Authors: Shahrour MA, Ashhab M, Edvardson S, Gur M, Abu-Libdeh B, Elpeleg O

Abstract
Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. We used whole exome analysis to study the molecular basis of hypomyelinating leukodystrophy in two sibs from a consanguineous family. A homozygous mutation, c.3068+5G>A, was identified in the ATRN gene, with the consequent insertion of an intronic sequence into the patients' cDNA and a predicted premature termination of the ATRN polypeptide. ATRN encodes Attractin, which was previously shown to play a critical role in central myelination. Several spontaneous ATRN rodent mutants exhibited impaired myelination which was attributed to oxidative stress and accelerated apoptosis. ATRN can now be added to the growing list of genes associated with hypomyelinating leukodystrophy. The disease seems to be confined to the CNS; however, given the young age of our patients, longer follow-up may be required.

PMID: 28493104 [PubMed - as supplied by publisher]

Progressive hereditary spastic paraplegia caused by a homozygous KY mutation.

Eur J Hum Genet. 2017 May 10;:

Authors: Yogev Y, Perez Y, Noyman I, Madegem AA, Flusser H, Shorer Z, Cohen E, Kachko L, Michaelovsky A, Birk R, Koifman A, Drabkin M, Wormser O, Halperin D, Kadir R, Birk OS

Abstract
Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.European Journal of Human Genetics advance online publication, 10 May 2017; doi:10.1038/ejhg.2017.85.

PMID: 28488683 [PubMed - as supplied by publisher]

Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort.

Am J Med Genet A. 2017 May 09;:

Authors: Malam F, Hartley T, Gillespie MK, Armour CM, Bariciak E, Graham GE, Nikkel SM, Richer J, Sawyer SL, Boycott KM, Dyment DA

Abstract
Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.

PMID: 28488422 [PubMed - as supplied by publisher]

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Cold Spring Harb Mol Case Stud. 2017 May;3(3):a001602

Authors: Uzilov AV, Cheesman KC, Fink MY, Newman LC, Pandya C, Lalazar Y, Hefti M, Fowkes M, Deikus G, Lau CY, Moe AS, Kinoshita Y, Kasai Y, Zweig M, Gupta A, Starcevic D, Mahajan M, Schadt EE, Post KD, Donovan MJ, Sebra R, Chen R, Geer EB

Abstract
Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

PMID: 28487882 [PubMed - in process]

Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines.

Sci Rep. 2017 May 09;7(1):1625

Authors: Mao X, Li K, Tang B, Luo Y, Ding D, Zhao Y, Wang C, Zhou X, Liu Z, Zhang Y, Wang P, Xu Q, Sun Q, Xia K, Yan X, Jiang H, Lu S, Guo J

Abstract
Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of "Epilepsy", which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.

PMID: 28487569 [PubMed - in process]

Sequencing of cancer cell subpopulations identifies micrometastases in a bladder cancer patient.

Oncotarget. 2017 Apr 21;:

Authors: Prado K, Zhang KX, Pellegrini M, Chin AI

Abstract
PURPOSE: Pathologic staging of bladder cancer patients remains a challenge. Standard-of-care histology exhibits limited sensitivity in detection of micrometastases, which can increase risk of cancer progression and delay potential adjuvant therapies. Here, we sought to develop a proof of concept novel molecular approach to improve detection of cancer micrometastasis.
EXPERIMENTAL DESIGN: We combined fluorescence activated cell sorting and next-generation sequencing and performed whole-exome sequencing of total cancer cells and cancer cell subpopulations in multiple tumor specimens and regional lymph nodes in a single patient with muscle-invasive urothelial carcinoma of the bladder following radical cystectomy.
RESULTS: Mean allele frequency analysis demonstrated a significant correlation between primary tumor cancer cells and cancer cells isolated from the lymph nodes, confirming lymph node disease despite negative pathologic staging. RNA-sequencing revealed intratumoral heterogeneity as well as enrichment for immune system and lipid metabolism gene sets in the micrometastatic cancer cell subpopulations.
CONCLUSIONS: Our analysis illustrates how next-generation sequencing of cancer cell subpopulations may be utilized to enrich for cancer cell markers and enhance detection of bladder cancer micrometastases to improve pathologic staging and provide insight into cancer cell biology.

PMID: 28487492 [PubMed - as supplied by publisher]

A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism.

Am J Hum Genet. 2017 Mar 02;100(3):506-522

Authors: Paolini NA, Attwood M, Sondalle SB, Vieira CM, van Adrichem AM, di Summa FM, O'Donohue MF, Gleizes PE, Rachuri S, Briggs JW, Fischer R, Ratcliffe PJ, Wlodarski MW, Houtkooper RH, von Lindern M, Kuijpers TW, Dinman JD, Baserga SJ, Cockman ME, MacInnes AW

Abstract
Ribosomal protein (RP) gene mutations, mostly associated with inherited or acquired bone marrow failure, are believed to drive disease by slowing the rate of protein synthesis. Here de novo missense mutations in the RPS23 gene, which codes for uS12, are reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features. One individual additionally presents with intellectual disability and autism spectrum disorder. The amino acid substitutions lie in two highly conserved loop regions of uS12 with known roles in maintaining the accuracy of mRNA codon translation. Primary cells revealed one substitution severely impaired OGFOD1-dependent hydroxylation of a neighboring proline residue resulting in 40S ribosomal subunits that were blocked from polysome formation. The other disrupted a predicted pi-pi stacking interaction between two phenylalanine residues leading to a destabilized uS12 that was poorly tolerated in 40S subunit biogenesis. Despite no evidence of a reduction in the rate of mRNA translation, these uS12 variants impaired the accuracy of mRNA translation and rendered cells highly sensitive to oxidative stress. These discoveries describe a ribosomopathy linked to uS12 and reveal mechanistic distinctions between RP gene mutations driving hematopoietic disease and those resulting in developmental disorders.

PMID: 28257692 [PubMed - indexed for MEDLINE]

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.

Am J Hum Genet. 2017 Mar 02;100(3):537-545

Authors: Osborn DP, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y, Manzini MC

Abstract
Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

PMID: 28190459 [PubMed - indexed for MEDLINE]

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium.

Am J Hum Genet. 2016 Jun 02;98(6):1067-76

Authors: Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, Berg JS, Biswas S, Bowling KM, Conlin LK, Cooper GM, Dorschner MO, Dulik MC, Ghazani AA, Ghosh R, Green RC, Hart R, Horton C, Johnston JJ, Lebo MS, Milosavljevic A, Ou J, Pak CM, Patel RY, Punj S, Richards CS, Salama J, Strande NT, Yang Y, Plon SE, Biesecker LG, Rehm HL

Abstract
Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.

PMID: 27181684 [PubMed - indexed for MEDLINE]

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GZF1 Mutations Expand the Genetic Heterogeneity of Larsen Syndrome.

Am J Hum Genet. 2017 May 04;100(5):831-836

Authors: Patel N, Shamseldin HE, Sakati N, Khan AO, Softa A, Al-Fadhli FM, Hashem M, Abdulwahab FM, Alshidi T, Alomar R, Alobeid E, Wakil SM, Colak D, Alkuraya FS

Abstract
Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

PMID: 28475863 [PubMed - in process]

A cumulative effect involving malfunction of the PTH1R and ATP4A genes explains a familial gastric neuroendocrine tumor with hypothyroidism and arthritis.

Gastric Cancer. 2017 May 04;:

Authors: Calvete O, Herraiz M, Reyes J, Patiño A, Benitez J

Abstract
BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production.
METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin.
RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1R p.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis.
CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.

PMID: 28474257 [PubMed - as supplied by publisher]

Use of Clinical Exome Sequencing in Isolated Congenital Heart Disease.

Circ Cardiovasc Genet. 2017 Jun;10(3):

Authors: Zahavich L, Bowdin S, Mital S

PMID: 28473349 [PubMed - in process]

A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID syndrome in a patient with a novel NFKB2 mutation.

J Clin Endocrinol Metab. 2017 May 03;:

Authors: Lal RA, Bachrach LK, Hoffman AR, Inlora J, Rego S, Snyder MP, Lewis DB

Abstract
Context: DAVID syndrome (Deficient Anterior pituitary with Variable Immune Deficiency) is a rare disorder in which children present with symptomatic ACTH deficiency preceded by hypogammaglobulinemia from B-cell dysfunction with recurrent infections, termed common variable immunodeficiency (CVID). Subsequent whole exome sequencing studies have revealed germline heterozygous C-terminal mutations of NFKB2 as either a cause of DAVID syndrome or of CVID without clinical hypopituitarism. However, to the best of our knowledge there have been no cases in which the endocrinopathy has presented in the absence of a prior clinical history of CVID.
Case Description: A previously healthy 7 year-old boy with no history of clinical immunodeficiency, presented with profound hypoglycemia and seizures. He was found to have secondary adrenal insufficiency and was started on glucocorticoid replacement. An evaluation for autoimmune disease, including for anti-pituitary antibodies, was negative. Evaluation unexpectedly revealed hypogammaglobulinemia (decreased IgG, IgM, and IgA). He had moderately reduced serotype-specific IgG responses following pneumococcal polysaccharide vaccine. Subsequently, he was found to have growth hormone (GH) deficiency. Six years after initial presentation, whole exome sequencing revealed a novel de novo heterozygous NFKB2 missense mutation c.2596A>C (p.Ser866Arg) in the C-terminal region predicted to abrogate the processing of the p100 NFKB2 protein to its active p52 form.
Conclusions: Isolated early-onset ACTH deficiency is rare and C-terminal region NFKB2 mutations should be considered as an etiology even in the absence of a clinical history of CVID. Early immunologic evaluation is indicated in the diagnosis and management of isolated ACTH deficiency.

PMID: 28472507 [PubMed - as supplied by publisher]

Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing.

Genet Med. 2017 May 04;:

Authors: Haggerty CM, James CA, Calkins H, Tichnell C, Leader JB, Hartzel DN, Nevius CD, Pendergrass SA, Person TN, Schwartz M, Ritchie MD, Carey DJ, Ledbetter DH, Williams MS, Dewey FE, Lopez A, Penn J, Overton JD, Reid JG, Lebo M, Mason-Suares H, Austin-Tse C, Rehm HL, Delisle BP, Makowski DJ, Mehra VC, Murray MF, Fornwalt BK

Abstract
PurposeArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained.MethodsIndividuals (n = 30,716) underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes.ResultsEighteen subjects had pLOF variants; none of these had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram, one had a minor diagnostic criterion; the rest were normal. A total of 184 subjects had VUS, none of whom had an ARVC diagnosis. The proportion of subjects with VUS with major (4%) or minor (13%) electrocardiogram diagnostic criteria did not differ from that of variant-negative controls. ICD-9 codes showed no difference in defibrillator use, electrophysiologic abnormalities or nonischemic cardiomyopathies in patients with pLOF or VUSs compared with controls.ConclusionpLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.GENETICS in MEDICINE advance online publication, 4 May 2017; doi:10.1038/gim.2017.40.

PMID: 28471438 [PubMed - as supplied by publisher]