A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors.

Mol Genet Genomic Med. 2017 Mar;5(2):130-140

Authors: Mitra AK, Dodge J, Van Ness J, Sokeye I, Van Ness B

Abstract
BACKGROUND: Kleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies.
METHODS: In this report, we used next-generation sequencing (exome sequencing and high-throughput RNA sequencing) in a patient and his parents to identify causative genetic variants followed by pharmacogenomics-guided clinical decision-making for making positive changes toward his treatment strategies. The patient had an early autism diagnosis and showed significant regressive behaviors and physical aberrations at age 23.
RESULTS: Exome sequencing identified a novel, de novo splice site variant NM_024757.4: c.2750-1G>T in EHMT1, a candidate gene for Kleefstra syndrome, in the patient that results in exon skipping and downstream frameshift and termination. Gene expression results from the patient showed, when compared to his parents, there was a significant decreased expression of several reported gene variants associated with autism risk. Further, using a pharmacogenomics genotyping panel, we discovered that the patient had the CYP2D6 nonfunctioning variant genotype *4/*4 that results in very low metabolic activity on a number of psychotropic drugs, including fluvoxamine which he was prescribed. As reported here, a change in psychotropic drugs and intense behavior therapies resulted in a significant reversal of the regressive behaviors and physical aberrations.
CONCLUSION: These results demonstrate an individualized approach that integrated genetic information and behavior therapies, resulting in a dramatic improvement in regressive behaviors associated with KS.

PMID: 28361099 [PubMed - in process]

Building a family network from genetic testing.

Mol Genet Genomic Med. 2017 Mar;5(2):122-129

Authors: Leppig KA, Thiese HA, Carrel D, Crosslin DR, Dorschner MO, Gordon AS, Hartzler A, Ralston J, Scrol A, Larson EB, Jarvik GP

Abstract
BACKGROUND: Genetic testing has multigenerational and familial repercussions. However, the "trickle-down effect" of providing genetic counseling and testing to family members at risk after an initial identification of a pathogenic variant in a medically actionable gene has been poorly understood.
METHODS: Three probands were identified during the pharmacogenetics research phase of eMERGEII (electronic MEdical Record and Genomics, phase II) to have variants in genes associated with autosomal dominant adult-onset disorders determined to be actionable by the American College of Medical Genetics (ACMG). Two of the three probands had variants that were classified as pathogenic and the third proband had a variant ultimately classified of uncertain significance, but of concern due to the proband's own phenotype. All probands had additional family members at risk for inheriting the variant. Two of the three probands had family members who received their medical care from the same health care system, Group Health Cooperative (GHC). It was recommended that the proband contact their family members at risk to be referred to genetic counseling for consideration of genetic testing.
RESULTS: The two probands with pathogenic variants contacted some of their family members at risk. Individuals contacted included children and adult grandchildren, particularly if they received their medical care at GHC. To the best of our knowledge, siblings and more distant relatives at risk were not informed by the proband of their genetic risk.
CONCLUSIONS: Establishing a family network is essential to disseminate knowledge of genetic risk. These three initial cases describe our experience of contacting eMERGE participants with identified variants, providing the probands with appropriate genetic counseling and care coordination, and recommendations for contacting family members at risk. Greater challenges were observed for coordinating genetics care for family members and extending the family network to include other relatives at risk.

PMID: 28361098 [PubMed - in process]

Refining Pharmacologic Research to Prevent and Treat Spontaneous Preterm Birth.

Front Pharmacol. 2017;8:118

Authors: Manuck TA

PMID: 28360854 [PubMed - in process]

[TRPM7 and tumor].

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2016 Mar 28;41(3):333-6

Authors: Zhao M, Luo C, Wang Y, Wang J

Abstract
The transient receptor potential (TRP) family is a superfamily of cation channels located on the cell membrane. Transient receptor potential melastatin (TRPM) 7, a member of the TRPM subgroup of TRP channels, and was the most representative biofunctional membrane protein. It conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. It is capable of phosphorylating TRPM7 and other substrates. TRPM7 can mediate sensory transmission, regulate cellular Ca2+ and Mg2+ homeostasis and affect embryonic development. Abnormal expression and/or activity of the TRPM7 channel kinase is involved in a variety of diseases, particularly the development and progression of cancer. TRPM7 channel-kinase is essential for cellular processes, such as proliferation, survival, differentiation, growth, and migration.

PMID: 27033800 [PubMed - indexed for MEDLINE]

[Effect of polymorphisms of NF-κB and PXR on platinum-based chemotherapy for non-small cell lung cancer].

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2016 Mar 28;41(3):233-7

Authors: Zhou Y, Yang P, Liu Y, Wang L

Abstract
OBJECTIVE: To investigate the effect of polymorphisms of NF-κB rs230521, NF-κB rs4648068 and pregnane X receptor (PXR) rs3814058 on platinum-based chemotherapy for non-small cell lung cancer patients. 

METHODS: We collected 262 cases of non-small cell lung cancer patients, and then analyzed the genotypes of NF-κB and PXR by MassARRAY method. The impact of polymorphisms on efficacy, gastrointestinal toxicity and hematological toxicity was analyzed by logistic regression.

RESULTS: Compared to patients with GG genotype, patients with NF-κB rs230521 CC genotype had the higher risk to suffer hematological toxicity (OR=3.485, P=0.011). Patients with PXR rs3814058 CC and CT genotype exhibited higher possibility to suffer hematological toxicity than those with TT (OR=2.045, P=0.048). Polymorphism of NF-κB rs4648068 did not show significant effect on chemotherapy efficacy and occurrence of gastrointestinal toxicity and hematological toxicity.

CONCLUSION: Patients with NF-κB rs230521 CC, PXR rs3814058 CC and CT had higher risk to suffer hematological toxicity during platinum-based chemotherapy for non-small cell lung cancer. A rational dosage and course of treatment should be chosen to protect the patients with high risk genotype suffering hematological toxicity during their platinum-based therapy.

PMID: 27033785 [PubMed - indexed for MEDLINE]

Logistic ex Vivo Lung Perfusion for Hyperimmunized Patients.

Ann Thorac Surg. 2016 Sep;102(3):e205-6

Authors: De Wolf J, Puyo P, Bonnette P, Roux A, Le Guen M, Parquin F, Chapelier A, Sage E

Abstract
Hyperimmunized patients have restricted access to lung transplantation because of the low rate of donor lung availability. Sensitization to human leukocyte antigen is associated with acute rejection, allograft dysfunction, and decreased survival. Prospective crossmatching could allow matching a lung graft with the recipient; however, such a strategy would increase graft ischemia, with a worse impact on the long-term results of lung transplantation. We used logistic ex vivo lung perfusion for 3 patients at the Foch Hospital while waiting for a negative result of the prospective crossmatching and then moved forward to lung transplantation. All patients are alive 3 years after bilateral lung transplantation.

PMID: 27549543 [PubMed - indexed for MEDLINE]

Development and Validation of Clinical Whole-Exome and Whole-Genome Sequencing for Detection of Germline Variants in Inherited Disease.

Arch Pathol Lab Med. 2017 Mar 31;:

Authors: Hegde M, Santani A, Mao R, Ferreira-Gonzalez A, Weck K, Voelkerding K

Abstract
CONTEXT: - With the decrease in the cost of sequencing, the clinical testing paradigm has shifted from single gene to gene panel and now whole-exome and whole-genome sequencing. Clinical laboratories are rapidly implementing next-generation sequencing-based whole-exome and whole-genome sequencing. Because a large number of targets are covered by whole-exome and whole-genome sequencing, it is critical that a laboratory perform appropriate validation studies, develop a quality assurance and quality control program, and participate in proficiency testing.
OBJECTIVE: - To provide recommendations for whole-exome and whole-genome sequencing assay design, validation, and implementation for the detection of germline variants associated in inherited disorders.
DATA SOURCES: - An example of trio sequencing, filtration and annotation of variants, and phenotypic consideration to arrive at clinical diagnosis is discussed.
CONCLUSIONS: - It is critical that clinical laboratories planning to implement whole-exome and whole-genome sequencing design and validate the assay to specifications and ensure adequate performance prior to implementation. Test design specifications, including variant filtering and annotation, phenotypic consideration, guidance on consenting options, and reporting of incidental findings, are provided. These are important steps a laboratory must take to validate and implement whole-exome and whole-genome sequencing in a clinical setting for germline variants in inherited disorders.

PMID: 28362156 [PubMed - as supplied by publisher]

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.

J Am Coll Cardiol. 2017 Apr 04;69(13):1653-1665

Authors: Belkaya S, Kontorovich AR, Byun M, Mulero-Navarro S, Bajolle F, Cobat A, Josowitz R, Itan Y, Quint R, Lorenzo L, Boucherit S, Stoven C, Di Filippo S, Abel L, Zhang SY, Bonnet D, Gelb BD, Casanova JL

Abstract
BACKGROUND: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM.
OBJECTIVES: This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children.
METHODS: We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes.
RESULTS: We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3).
CONCLUSIONS: Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.

PMID: 28359509 [PubMed - in process]

Anabolic steroid use.

BMJ. 2016 Oct 13;355:i5023

Authors: Brooks JH, Ahmad I, Easton G

PMID: 27737851 [PubMed - indexed for MEDLINE]

Adverse effects of nephrectomy.

Pediatr Nephrol. 2016 07;31(7):1195

Authors: Cozzi DA, Ceccanti S, Cozzi F

PMID: 27025374 [PubMed - indexed for MEDLINE]

Carbon nanotubes: Properties, biomedical applications, advantages and risks in patients and occupationally-exposed workers.

Int J Immunopathol Pharmacol. 2015 Mar;28(1):4-13

Authors: Lamberti M, Pedata P, Sannolo N, Porto S, De Rosa A, Caraglia M

Abstract
Since the beginning of the 21st century, carbon-based nanomaterials (CNTs) have been introduced in pharmacy and medicine for drug delivery system in therapeutics. CNTs have proved able to transport a wide range of molecules across membranes and into living cells; therefore, they have attracted great interest in biomedical applications such as advanced imaging, tissue regeneration, and drug or gene delivery. Although there are many data on the advantages in terms of higher efficacy and less adverse effects, several recent findings have reported unexpected toxicities induced by CNTs. The dose, shape, surface chemistry, exposure route, and purity play important roles in these differential toxicities. Mapping these risks as well as understanding their molecular mechanisms is a crucial step in the development of any CNT-containing nanopharmaceuticals. This paper seeks to provide a comprehensive review of all articles published on cellular response to CNTs, underlining their therapeutic applications and possible toxicity in patients and occupationally exposed workers.

PMID: 25816400 [PubMed - indexed for MEDLINE]