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Supplementary Figure 1 from Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer

Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer. (Cancer Res 2006; 66(18): 9017-25)

Supplementary Figure Legends and Tables 1-2 from Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer

Supplementary Figure 2 from Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer

D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient’s father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.

Pyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis manifesting as painful inflammatory plaques and ulcers, frequently associated with inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, and acute myeloid leukemia.1 We present a case of a young woman with a novel mutation in NFkB1 who experienced common variable immunodeficiency (CVID) and severe recurrent PG episodes.

Background The OncoScan microarray assay (OMA) using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP) loci enabled the detection of cytogenomic abnormalities of chromosomal imbalances and pathogenic copy number variants (pCNV). The small size of molecular inversion probes is optimal for SNP genotyping of fragmented DNA from fixed tissues. This retrospective study evaluated the clinical utility of OMA as a uniform platform to detect cytogenomic abnormalities for pregnancy loss from fresh and fixed tissues of products of conception (POC). Results Fresh specimens of POC were routinely subjected to cell culture and then analyzed by karyotyping. POC specimens with a normal karyotype (NK) or culture failure (CF) and from formalin-fixed paraffin-embedded (FFPE) tissues were subjected to DNA extraction for OMA. The abnormality detection rate (ADR) by OMA on 94 cases of POC-NK, 38 cases of POC-CF, and 35 cases of POC-FFPE tissues were 2% (2/94), 26% (10/38), and 57% (20/35), respectively. The detected cytogenomic abnormalities of aneuploidies, triploidies and pCNV accounted for 50%, 40% and 10% in POC-CF and 85%, 10% and 5% in POC-FFPE, respectively. False negative result from cultured maternal cells and maternal cell contamination were each detected in one case. OMA on two cases with unbalanced structural chromosome abnormalities further defined genomic imbalances and breakpoints. Conclusion OMA on POC-CF and POC-FFPE showed a high diagnostic yield of cytogenomic abnormalities. This approach circumvented the obstacles of CF from fresh specimens and fragmented DNA from fixed tissues and provided a reliable and effective platform for detecting cytogenomic abnormalities and monitoring true fetal result from maternal cell contamination.

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.

Melanocortin 4 receptor gene (MC4R) mutations result in early-onset obesity, but it is unclear how they affect abdominal fat distribution, intrahepatic fat, and related metabolic sequelae. 484 overweight/obese (BMI >85th percentile for age, sex, and height) youth (6-21 years) were screened for functionally damaging, rare variants (minor allele frequency Disclosure D. Trico: None. A.E. Bale: None. S. Caprio: None. N. Santoro: None.

The single-exon gene CEBPA encodes for CCAAT/enhancer binding protein-α, a transcription factor essential for granulocyte differentiation. In acute myeloid leukemia (AML), CEBPA mutations occur at ...

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

Thoracic aortic aneurysm is a typically silent disease characterized by a lethal natural history. Since the discovery of the familial nature of thoracic aortic aneurysm and dissection (TAAD) almost 2 decades ago, our understanding of the genetics of this disorder has undergone a transformative amplification. To date, at least 37 TAAD-causing genes have been identified and an estimated 30% of the patients with familial nonsyndromic TAAD harbor a pathogenic mutation in one of these genes. In this review, we present our yearly update summarizing the genes associated with TAAD and the ensuing clinical implications for surgical intervention. Molecular genetics will continue to bolster this burgeoning catalog of culprit genes, enabling the provision of personalized aortic care.

Background & Aims Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. Methods We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. Results Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. Conclusions Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. Lay summary We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.

// Amruta Phatak 1 , Mohammad Athar 2 , James A. Crowell 3 , David Leffel 4 , Brittney-Shea Herbert 1 , Allen E. Bale 5 and Levy Kopelovich 6 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA 3 NCI-DCTD-DTP, Bethesda, MD, USA 4 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA 5 Department of Genetics, Yale School of Medicine, New Haven, CT, USA 6 Department of Medicine, Weill Cornell Medical College, New York, NY, USA Correspondence to: Levy Kopelovich, email: kopelovichl@gmail.com Allen E. Bale, email: allen.bale@yale.edu Keywords: Gorlin syndrome; basal cell carcinoma; patched; HH signaling; rapamycin Received: December 09, 2018 Accepted: January 11, 2019 Published: February 15, 2019 ABSTRACT Studies of dominantly heritable cancers enabled insights about tumor progression. BCNS is a dominantly inherited disorder that is characterized by developmental abnormalities and postnatal neoplasms, principally BCCs. We performed an exploratory gene expression profiling of primary cell cultures derived from clinically unaffected skin biopsies of BCNS gene-carriers ( PTCH1 +/- ) and normal individuals. PCA and HC of untreated keratinocytes or fibroblasts failed to clearly distinguish BCNS samples from controls. These results are presumably due to the common suppression of canonical HH signaling in vitro . We then used a relaxed threshold (p-value

Purpose Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss. Methods A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. Results ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases. Conclusion These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

PurposePregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of whole exome sequencing (WES) in identifying the genetic etiology for pregnancy loss.MethodsA cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy number variants were selected for WES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated.ResultsWES detected six pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multi-system abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders and renal diseases.ConclusionThese results supported the clinical utility of WES for detecting monogenic etiology of pregnancy loss. The identification of disease associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss.A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated.ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases.These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

Focal segmental glomerulosclerosis (FSGS) is a podocytopathy leading to kidney failure, whose molecular cause frequently remains unresolved. Here, we describe a rare MYO9A loss of function nonsense heterozygous mutation (p.Arg701∗) as a possible contributor to disease in a sibling pair with familial FSGS/proteinuria. MYO9A variants of uncertain significance were identified by whole exome sequencing in a cohort of 94 biopsy proven patients with FSGS. MYO9A is an unconventional myosin with a Rho-GAP domain that controls epithelial cell junction assembly, crosslinks and bundles actin and deactivates the small GTPase protein encoded by the RHOA gene. RhoA activity is associated with cytoskeleton regulation of actin stress fiber formation and actomyosin contractility. Myo9A was detected in mouse and human podocytes in vitro and in vivo. Knockin mice carrying the p.Arg701∗ MYO9A (Myo9AR701X) generated by gene editing developed proteinuria, podocyte effacement and FSGS. Kidneys and podocytes from Myo9AR701X/+ mutant mice revealed Myo9A haploinsufficiency, increased RhoA activity, decreased Myo9A-actin-calmodulin interaction, impaired podocyte attachment and migration. Our results indicate that Myo9A is a novel component of the podocyte cytoskeletal apparatus that regulates RhoA activity and podocyte function. Thus, Myo9AR701X/+ knock-in mice recapitulate the proband FSGS phenotype, demonstrate that p.R701X Myo9A is an FSGS-causing mutation in mice and suggest that heterozygous loss-of-function MYO9A mutations may cause a novel form of human autosomal dominant FSGS. Hence, identification of MYO9A pathogenic variants in additional individuals with familial or sporadic FSGS is needed to ascertain the gene contribution to disease.

Background: GATA3 encodes a transcription factor critical for embryonic development of the parathyroid glands, kidney, inner ear, thymus, and the central nervous system. Heterozygous loss-of-function mutations in GATA3 are associated with hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome). Clinical Case: A 12 yo male with left hip pain underwent a closed reduction for left slipped capital femoral epiphysis. The pre-op evaluation revealed hypocalcemia (serum Ca 7.7 mg/dL; nl: 8.8-10.2), creatinine 0.46 mg/dL (0.5-1.0), TSH 3.16 uU/mL (0.3-4.2), FT4 1.36 ng/dL (0.8-1.8). Oral calcium and vitamin D supplementation was begun, and 2 wks later, follow-up evaluation revealed serum Ca of 9.4 mg/dL, intact PTH 4.6 pg/mL (10-69), phosphorus 5.9 mg/dL (3.3-5.3), 25-OHD 26 ng/mL (30-100), and a normal chromosomal microarray. Bone density (DXA) Z-scores for hip and spine were -1.7 and 0.8, respectively. At age 13 he underwent bilateral osteotomy due to bilateral hip dysplasia and removal of hardware the next year. At age 15 he underwent left total hip replacement for avascular necrosis. In the post-operative period hypocalcemia recurred (5.9-6.7mg/dL), and he was referred for endocrine evaluation. He was of mixed African American and Puerto-Rican descent. He had difficulties in school and required eyeglasses and hearing aids. Past history included congenital scoliosis (right T11-12 rib fusion, wedged L1 vertebra, and incomplete fusion of posterior elements of L4 and L5), a small right kidney (per ultrasound examination), bilateral orchiopexy for undescended testicles (age 2), diagnoses of ADHD (at age 5); sensorineural hearing loss and psoriasis (age 12), and gastroesophageal reflux (age13). Multiple paternal family members were reported to have abnormal calcium levels and hearing/vision problems, but no known diagnosis. On exam, he had no facial dysmorphism, but left supernumerary nipples, lumbar lordosis and thoracic kyphosis, and clinodactyly. He had achieved Tanner 5 secondary sexual characteristics. There was no Chvostek’s sign. Laboratory investigation revealed Ca 7.9 mg/dL, phosphorus 5.9 mg/dL (3.1-4.7), alkaline phosphatase 123 U/L (50-380), 25-OHD 32 ng/mL, intact PTH 10.2 pg/mL. Treatment with calcium carbonate and calcitriol was begun. Whole exome sequencing identified a heterozygous mutation in GATA3 (c.1061C>T, p.Pro354Leu), predicted to be damaging. This variant has not been reported in literature or public database to our knowledge. Conclusion: This case highlights the importance of genetic testing in the setting of unexplained hypoparathyroidism, and identifies a likely novel mutation in GATA3, providing a basis to counsel the family and encourage medical follow up of suspected family members. References: Barakat, A., et al., Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61-64, 1977

Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.

Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults.In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging.In Caucasian youth, the minor allele (C) was associated with HFF% in (P=0.003), fasting insulin (P=0.03), area under the curve of glucose (P=0.03), and lower degree of whole-body insulin sensitivity (P=0.01) independent of age, gender, and body mass index z-score. A partial correlation showed that the association between the rs626283 variant and insulin resistance was driven by the presence of hepatic steatosis (P=0.009). However, there was no association between the rs626283 and hepatic steatosis among Hispanic and African American children and youth. The association between the rs626283 in the MBOAT7 gene among Caucasians was independent of the PNPLA3 rs738409, GCKR 1260326, and TM6SF2 rs58542926 (P=0.01). The four polymorphisms combined explained~19% of the HFF% in Caucasian obese children and adolescents.The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents.

Introduction Basal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early-onset BCC (under age 40) and explored the potential role of ultraviolet (UV) radiation exposure and estrogen-related exposures in the BMI-BCC relationship. Methods BCC cases (n = 377) were identified through a central dermatopathology facility in Connecticut. Control subjects (n = 389) with benign skin conditions were randomly sampled from the same database and frequency matched to cases on age (median = 36, interquartile range 33–39), gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. Results Adult BMI was inversely associated with early-onset BCC (obese vs. normal OR = 0.43, 95% CI = 0.26–0.71). A similar inverse association was present for BMI at age 18 (OR = 0.54, 95% CI = 0.34–0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among women only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm = 1.00, 95% CI = 0.98–1.02). Conclusions We found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures or estrogen-related exposures in women.

Background: Array comparative genomic hybridization (aCGH), karyotyping and fluorescence in situ hybridization (FISH) analyses have been used in a clinical cytogenetic laboratory. A systematic analysis on diagnostic findings of cytogenomic abnormalities in current prenatal and pediatric settings provides approaches for future improvement. Methods: A retrospective analysis was performed on abnormal findings by aCGH, karyotyping, and FISH from 3,608 prenatal cases and 4,509 pediatric cases during 2008–2017. The diagnostic accuracy was evaluated by comparing the abnormality detection rate (ADR) and the relative frequency (RF) of different types of cytogenomic abnormalities between prenatal and pediatric cases. A linear regression correlation between known prevalence and ADR of genomic disorders was used to extrapolate the prevalence of other genomic disorders. The diagnostic efficacy was estimated as percentage of detected abnormal cases by expected abnormal cases from served population. Results: The composite ADR for numerical chromosome abnormalities, structural chromosome abnormalities, recurrent genomic disorders, and sporadic pathogenic copy number variants (pCNVs) in prenatal cases were 13.03%, 1.77%, 1.69%, and 0.9%, respectively, and were 5.13%, 2.84%, 7.08%, and 2.69% in pediatric cases, respectively. The chromosomal abnormalities detected in prenatal cases (14.80%) were significantly higher than that of pediatric cases (7.97%) (p < 0.05), while the pCNVs detected in prenatal cases (2.59%) were significantly lower than that of pediatric cases (9.77%) (p < 0.05). The prevalence of recurrent genomic disorders and total pCNVs was estimated to be 1/396 and 1/291, respectively. Approximately, 29% and 35% of cytogenomic abnormalities expected from the population served were detected in current prenatal and pediatric diagnostic practice, respectively. Conclusion: For chromosomal abnormalities, effective detection of Down syndrome (DS) and Turner syndrome (TS) and under detection of sex chromosome numerical abnormalities in both prenatal and pediatric cases were noted. For pCNVs, under detection of pCNVs in prenatal cases and effective detection of DiGeorge syndrome (DGS) and variable efficacy in detecting other pCNVs in pediatric cases were noted. Extend aCGH analysis to more prenatal cases with fetal ultrasonographic anomalies, enhanced non-invasive prenatal (NIPT) testing screening for syndromic genomic disorders, and better clinical indications for pCNVs are approaches that could improve diagnostic yield of cytogenomic abnormalities.

Background: AMP-activated protein kinase (AMPK) is implicated in several aspects of lipid metabolism including the suppression of de novo lipogenesis, promotion of fatty acid oxidation, and regulation of adipose tissue biology. We report a patient with severe hypertriglyceridemia harboring a heterozygous mutation in the PRKAA1 gene which codes for the α1-subunit of AMPK. Clinical case: A 22-year-old Mexican woman with history of morbid obesity and T2DM presented with eruptive xanthomas in the upper and lower extremities, back, and chest. VS:141/80, P 86, RR 20, 122 kg BMI 43.42 kg/m2. She was misdiagnosed on multiple occasions and had been treated with steroids until a biopsy revealed foamy histiocytes consistent with xanthomas. A lipid panel showed Triglycerides 8,513 mg/dl (0-150 mg/dl) Cholesterol 555 mg/dl (0-199 mg/dl) HDL 29 mg/dl (≥ 41 mg/dl) Direct LDL 44 (0-99). There was no family history of hyperlipidemia. After ~24-months of follow-up abnormal lipid levels persisted: Triglycerides 4527-8513 mg/dl (0-150 mg/dl) Cholesterol 408-555 mg/dl (0-199 mg/dl) HDL 22-29 mg/dl (≥ 41 mg/dl). She had microalbuminuria 87.7 mcg/mg (0-29.9 mcg/mg) and an HbA1c of 7.8%. She endorsed depression and was inconsistent with her diet due to insatiable appetite but reported medication compliance. Lipoprotein electrophoresis showed a pattern consistent with type IV Hyperlipoproteinemia. Sequencing of lipid metabolism genes revealed no abnormalities but upon whole exome scanning she was found to have a heterozygous nonsense variant in PRKAA1 (exon4:c.C394T:p.Q132X) which codes for the α1-subunit of AMPK resulting in a premature stop codon. We hypothesize that this variant results in defective AMPK activity, and given the role of AMPK in lipid and adipose tissue metabolism, it may result in disinhibition of lipogenesis, reduced fatty acid oxidation, and altered adipose tissue biology, together promoting extreme hypertriglyceridemia. Conclusion: This is the first case to implicate a PRKAA1 gene mutation as a cause of severe hypertriglyceridemia in humans.

Objective Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by elevated serum calcium with relatively low urinary calcium excretion. It typically results from an altered set point in calcium homeostasis originating from mutations in the calcium-sensing receptor (CASR), AP2S1, or GNA11 genes, which encode for the calcium-sensing receptor (CaSR), adaptor-related protein complex 2, and G-protein alpha-11 subunit, respectively. Despite numerous reports of novel variants in these genes associated with FHH, new variants continue to be discovered. Methods We describe a 20-year-old man with a family history of hypercalcemia who had clinical findings compatible with FHH and no evidence of multiple endocrine neoplasia who underwent CASR gene sequencing for evaluation of hypercalcemia. Parathyroid gland single-photon emission computerized tomography scan was normal. Results CASR gene sequencing revealed a previously unreported heterozygous intronic variant at position 1608+3A>G (chromosome 3: 121994892) resulting in a 77-residue deletion. His mother has a history of bipolar disorder and hyperparathyroidism with an adenoma found on imaging, yet our patient had no evidence of adenoma and therefore no surgical intervention was recommended. Given that CaSR plays a role in parathyroid growth, some variants in CASR may ultimately lead to parathyroid hypertrophy and be mistaken for primary hyperparathyroidism. Conclusion Long-term clinical follow up will be helpful in understanding the ultimate effects of specific CASR mutations on parathyroid growth or progression to significant hypercalcemia.

Background Mitochondrial membrane protein associated neurodegeneration (MPAN) is the third most common subtype of neurodegeneration with brain iron accumulation (NBIA) and caused by mutations of the orphan gene C19ORF12 encoding a transmembrane mitochondrial protein. Like other NBIA disorders, the hallmark of neuropathology is iron deposition in the basal ganglia, but the clinical presentation is highly variable. Methods We present the relevant clinical history, neurological examination, electrophysiological and neuroimaging tests of a currently ten-year-old girl. The genetic analysis was carried out by exome sequencing focused on known NBIA and juvenile amyotrophic lateral sclerosis (ALS) genes. Results The patient presented at four years of age with progressive lower extremity weakness and generalized hypotonia. She was initially diagnosed with juvenile ALS based on clinical signs, negative brain magnetic resonance imaging (MRI) and electromyography findings. As the disease progressed, a repeat brain MRI showed iron deposition in the basal ganglia at nine years of age. Exome sequencing of genes known to be associated with NBIA revealed a compound heterozygous mutation of C19ORF12 gene. Conclusions A C19orf12 gene mutation should be considered in young children with clinical signs of progressive upper and lower motor neuron disease. Finding iron accumulation in the basal ganglia helps to focus the genetic testing, but it may not be apparent for several years.

Familial isolated pituitary adenoma (FIPA) is a rare genetic disorder. In a subset of FIPA families AIP germline mutations have been reported, but in most FIPA cases the exact genetic defect remains unknown. The present study aimed to determine the genetic basis of FIPA in a Brazilian family. Three siblings presented with isolated prolactin genes. Further mutation screening was performed using whole-exome sequencing and all likely causative mutations were validated by Sanger sequencing. In silico analysis and secreting pituitary adenoma diagnosed through clinical, biochemical and imaging testing. Sanger sequencing was used to genotype candidate prolactinoma-mutated additional predictive algorithms were applied to prioritize likely pathogenic variants. No mutations in the coding and flanking intronic regions in the MEN1, AIP and PRLR genes were detected. Whole-exome sequencing of three affected siblings revealed novel, predicted damaging, heterozygous variants in three different genes: RXRG, REXO4 and TH. In conclusion, the RXRG and TH possibly pathogenic variants may be associated with isolated prolactinoma in the studied family. The possible contribution of these genes to additional FIPA families should be explored.

Mutations in Kelch-like family member 7 (KLHL7) have recently been described as a cause of a constellation of clinical findings with descriptions of both a Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like, as well as a Bohring-Opitz syndrome (BOS)-like presentation. Here we report two siblings of Guatelmalan descent with a novel homozygous nonsense mutation (p.Arg326*) in KLHL7. These children have multiple dysmorphic features and developmental delay. Interestingly, their clinical traits inconsistently overlap both the CS/CISS1-like and BOS-like phenotypes, and the siblings also have subtle differences from each other, suggesting that clinicians need to be aware of the degree of variability in the presentations of these patients. Still, there is enough in common between patients with recessive KLHL7 mutations to define a novel multisystem disease that features various neurodevelopmental, musculoskeletal, dysmorphic, and other unique components. This report adds to the clinical features and disease-associated variants of the newly-recognized spectrum of KLHL7 mutations, and offers a new description, PERCHING, for the resulting syndrome.

Background Hereditary factors play an important etiologic role in thoracic aortic aneurysm and dissection (TAAD), with a number of genes proven to predispose to this condition. We initiated a clinical program for routine genetic testing of individuals for TAAD by whole exome sequencing (WES). Here we present our initial results. Methods The WES was performed in 102 patients (mean age 56.8 years; range 13 to 83; 70 males [68.6%]) with TAAD. The following 21-gene panel was tested by WES: ACTA2, ADAMTS10, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, ELN, FBLN4, FLNA, FBN1, FBN2, MYH11, MYLK, NOTCH1, PRKG1, SLC2A10, SMAD3, TGFB2, TGFBR1, TGFBR2. Results Seventy-four patients (72.5%) had no medically important genetic alterations. Four patients (3.9%) had a deleterious mutation identified in the FBN1, COL5A1, MYLK, and FLNA genes. Twenty-two (21.6%) previously unreported suspicious variants of unknown significance were identified in 1 or more of the following genes: FBN1 (n = 5); MYH11 (n = 4); ACTA2 (n = 2); COL1A1 (n = 2); TGFBR1 (n = 2); COL3A1 (n = 1); COL5A1 (n = 1); COL5A2 (n = 1); FLNA (n = 1); NOTCH1 (n = 1); PRKG1 (n = 1); and TGFBR3 (n = 1). Identified mutations had implications for clinical management. Conclusions Routine genetic screening of patients with TAAD provides information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology. Analysis of large data sets of variants of unknown significance that include associated clinical features will help define the mutational spectrum of known genes underlying this phenotype and potential identify new candidate loci.

Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.

Summary Background Previous epidemiological studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) radiation, this has not been evaluated in existing epidemiological studies. Objectives To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. Methods Basal cell carcinoma cases (n = 380) and controls with benign skin conditions (n = 390) under 40 years of age were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage, during an in-person interview. Self-reported data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CIs) using unconditional multivariate logistic regression in the full sample and in women only. Results There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall [above median intake vs. no regular alcohol intake (OR 1·10, 95% CI 0·69–1·73)] or in women only (OR 1·21, 95% CI 0·73–2·01). Similarly, intake of red wine, white wine, beer or spirits and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (Pinteraction = 0·003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping CIs. Conclusions Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC.

RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.Asn221Ser mutation in RRM2B who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Through molecular modeling using the X-ray crystal structure of p53R2, we demonstrate that this mutation likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions. This report expands our knowledge of potential pathogenic RRM2B mutations as well as our understanding of the molecular function of p53R2 and its role in the pathogenesis of mitochondrial DNA depletion.

While next-generation genome sequencing can successfully guide cancer therapy, it can also reveal significant incidental findings that patients, families, and physicians may not be prepared to handle and may not want to know.

Thoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-β signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified.

Background— With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results— We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels ( P =0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions— Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

SummaryHereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08-36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90-20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37-5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer.

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and an increased risk for leukemia and cancer. Fifteen proteins thought to function in the repair of DNA interstrand crosslinks (ICLs) comprise what is known as the FA-BRCA pathway. Activation of this pathway leads to the monoubiquitylation and chromatin localization of FANCD2 and FANCI. It has previously been shown that FANCJ interacts with the mismatch repair (MMR) complex MutLα. Here we show that FANCD2 interacts with the MMR proteins MSH2 and MLH1. FANCD2 monoubiquitylation, foci formation and chromatin loading are greatly diminished in MSH2-deficient cells. Human or mouse cells lacking MSH2 or MLH1 display increased sensitivity and radial formation in response to treatment with DNA crosslinking agents. Studies in human cell lines and Drosophila mutants suggest an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair. Surprisingly, the interaction between MSH2 and MLH1 is compromised in multiple FA cell lines, and FA cell lines exhibit deficient MMR. These results suggest a significant role for MMR proteins in the activation of the FA pathway and repair of ICLs. In addition, we provide the first evidence for a defect in MMR in FA cell lines.

Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome-wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. A total of 300 000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom array. We performed a gene burden test with Bonferroni correction for the number of genes examined (P 0.05/14 904 = 3.36 × 10(-6) ). One gene, patched domain containing 2 (PTCHD2), yielded a statistically significant P-value of 2.5 × 10(-6) (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD.

Introduction: Venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) and pulmonary embolism (PE), is a cause of significant morbidity and mortality worldwide, with an overall incidence of about 10,000,000 cases per year. The majority of VTEs are believed to be attributable to genetic factors. Yet, the five established heritable thrombophilias of factor V Leiden (FVL), prothrombin (PT) gene mutation, antithrombin (AT) deficiency, protein C (PC) deficiency, and protein S (PS) deficiency comprise only a small portion of VTEs, suggesting that further genetic factors contributing to VTE risk are unrecognized. In our previously published study, we performed whole exome sequencing (WES) in 64 patients with VTE and developed a 55-gene extended thrombophilia panel which identified 40 pathogenic or likely pathogenic variants or variants of uncertain significance (VUS) involving 22 different genes. Here, we present updated data from an expanded patient cohort. Methods: Blood was obtained from 101 patients with VTE. Genomic DNA was extracted and WES performed; mean coverage of the exome was 100x with 98% of the exome covered >/= 20 times. Variants were filtered for an allele frequency of 7% in the GnomAD database. A targeted analysis of the 55 genes in the extended thrombophilia panel was then performed. Variants in these genes were classified according to ACGM criteria as pathogenic, likely pathogenic, VUS, benign or likely benign. The number of patients with pathogenic or likely pathogenic variants and VUS in VTE patients was compared to a control population of 237 patients who had WES performed for reason other than VTE. The results of WES were also compared to those of traditional laboratory-based thrombophilia testing. Further, 17 VUS underwent in silico protein modeling to evaluate structural modifications. Results: Of the 101-patient study population, 46 were men and 55 women; 62% were Caucasian, 22% African American and 5% Hispanic; 15% had unprovoked VTE, 71% had provoked, 12% had both; and 55% had first degree family members with VTE. WES and extended thrombophilia testing identified a pathogenic or likely pathogenic variant or VUS in 69/101 (68%) VTE patients compared to 6/237 (2.5%) controls, a statistically significant difference (p-value A total of 72 genetic variants (26 previously published and 46 novel) were identified in 30 genes in the extended thrombophilia panel. 18 variants were categorized as pathogenic or likely pathogenic and 54 as VUS. 32 patients had pathogenic or likely pathogenic variants in one or more of the major thrombophilia genes, with FVL being the most common, and AT and PS deficiency being more common than PT gene mutation (FVL, n=15; PT gene mutation, n=3; AT deficiency, n=5; PC deficiency, n=3; PS deficiency, n=6). Of pathogenic variants in major thrombophilia genes, 15 were previously reported in literature, while 13 were novel. Of the 52 VUS, 17 were subjected to in silico analysis, including protein modeling, which suggested impaired protein folding in 14 variants. Conclusions: WES and extended thrombophilia testing reveal a high frequency of pathogenic or likely pathogenic variants or VUS in VTE patients compared to controls. These variants demonstrate good concordance with traditional laboratory-based thrombophilia testing. Several novel pathogenic or likely pathogenic variants were identified. In silico studies and protein modeling suggest that many VUS identified by this approach are likely to be deleterious to protein function. The results may underlie a strong genetic component to VTE. Next steps include further characterization of VUS using protein modeling, biochemical analysis, and epidemiological and familial studies to understand potential roles these variants may play in thrombosis. Table. Table. Disclosures Camire: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy.

Nevus sebaceus (NS) is a congenital skin hamartoma that presents in childhood. Tumors may arise within these lesions over time. Mutations in the PTCH gene have been associated with both NS and some of the developing tumors. Only nine documented cases of basal cell carcinoma arising in nevus sebaceus in childhood are available. We present a case of an 8-year-old male with nevus sebaceus who developed a basal cell carcinoma. Evaluation for constitutional PTCH gene mutation and loss of heterozygosity (LOH) from the BCC within the NS did not reveal an underlying mutation. We further discuss the literature regarding prophylactic excision of NS.

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case–control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3′ variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case–control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01–1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62–1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P

BackgroundBasal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early- onset BCC and explored the potential role of ultraviolet (UV) radiation exposure as well as estrogen-related exposures in the BMI-BCC relationship.MethodsBCC cases (n=377) diagnosed under age 40 were identified through a central dermatopathology facility in Connecticut. Control subjects (n=389) were randomly sampled from the same database and frequency matched to cases on age, gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models.ResultsAdult BMI was inversely associated with early-onset BCC (obese vs. normal OR=0.43, 95% CI=0.26-0.71). A similar inverse association was present for BMI at age 18 (OR=0.54, 95% CI=0.34-0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among females only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm=1.00, 95% CI=0.98-1.02).ConclusionWe found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures in this population or estrogen-related exposures among only the females

Author(s): Cartmel, Brenda; Mayne, Susan T; Bale, Allen E; Gelernter, Joel; DeWan, Andrew; Leffell, David J; Pagoto, Sherry; Spain, Peter; Ferrucci, Leah M | Abstract: Growing evidence suggests some individuals may exhibit dependence to ultraviolet light, a known carcinogen; however, few studies have investigated predictors of tanning dependence (TD).A sub-set of early-onset basal cell carcinoma case-control study participants completed an online survey. The modified-Cut down, Annoyed, Guilty, Eye-opener (mCAGE) and a questionnaire based on the addiction criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (mDSM-IV-TR) were used to classify participants having‘Symptoms of TD’ if they met criteria for TD on both questionnaires, ‘Tendency for TD’ if met criteria on only one questionnaire, or ‘Not TD’. We also assessed lifetime alcohol dependence, nicotine dependence, seasonal affective disorder (SAD), ‘exercise addiction,’ and depression. We compared TD groups with multivariate logistic regression.499 individuals reported volitional tanning and 24.4% were classified as having ‘Symptoms of TD’ and 24.4% as having a ‘Tendency for TD’. Women were more likely to have ‘Symptoms of TD’ (odds ratio (OR)=6.93; 95% Confidence Interval (95% CI)=(3.36-14.27)) or a ‘Tendency for TD’ (OR=2.82; 95% CI=1.59-4.98) than men. Alcohol dependence (OR=6.55; 95% CI=3.19-13.42), alcohol abuse (OR=3.16; 95% CI=1.81-5.51), risk of ‘exercise addiction’ (OR=5.47; 95%=1.15-26.06) and SAD (OR=2.77; 95% CI=1.26-6.09) were all significant predictors for ‘Symptoms of TD’. Alcohol dependence (OR=3.66; 95% CI=1.84-7.31) and alcohol abuse (OR=2.60; 95% CI=1.53-4.41) were significant predictors for ‘Tendency for TD.’Knowledge of associations between TD and gender, alcohol dependence/abuse, SAD, and ‘exercise addiction’ may be helpful to practitioners in treating TD and for targeting skin cancer preventive interventions for those with TD.