👤 José Maria Valero

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. FCS is caused by biallelic loss-of-function variants in LPL or in 4 other genes encoding its cofactors and regulators, including LMF1 (lipase maturation factor 1). Variants in LMF1 are rare and present only in 1% to 2% of the FCS cases. To assess in 3 patients with severe hypertriglyceridemia and recurrent pancreatitis and in whom a homozygous LMF1 duplication, initially classified as a variant of uncertain significance (VUS) was identified, post-heparin LPL activity. We collected demographics, fasting lipid profiles, and body mass index, and performed next-generation sequencing using a targeted panel that included canonical FCS genes. A homozygous in-frame duplication in LMF1 (c.914₉₂₈dup; p.Ser309_Phe310dup) was identified. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines and cross-referenced with public archive of reports of the relationships among human variations and phenotypes (ClinVar), The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (HGMD), Leiden Open Variation Database (LOVD), The Single Nucleotide Polymorphism database (dbSNP), The Genome Aggregation Database (gnomAD), and in-house databases. LPL activity was assessed in post-heparin plasma using a radiometric assay. All 3 patients were homozygous for c.914₉₂₈dup (this variant was classified as a VUS) and exhibited markedly reduced LPL activity (<20% of normal). Clinical manifestations were consistent with FCS, including extreme triglyceride elevations and recurrent pancreatitis. One patient died from fulminant pancreatitis. The combined clinical, biochemical, and genetic evidence supports the reclassification of LMF1 c.914₉₂₈dup (p.Ser309_Phe310dup) as likely pathogenic according to ACMG/AMP guidelines and indicates its association with severe pancreatitis. Show less

Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Patients with metastatic HR+HER2- IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials. Show less

Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM. Show less

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder affecting several systems caused by a heterozygous deletion in the chromosomal region 7q11.23. A common interval that includes up to 17 genes reported so far is deleted in the great majority of patients. Elastin haploinsufficiency is responsible for the cardiovascular features, but the specific contribution of other deleted genes to the WBS phenotype remains unknown. We have fully characterised a gene commonly deleted in WBS, WBSCR14, previously reported in a truncated form as WS-bHLH. The WBSCR14 cDNA encodes an 852amino acid protein with a basic helix-loop-helix-leucine-zipper motif (bHLHZip) and a bipartite nuclear localisation signal (BNLS), suggesting a function as a transcription factor. WBSCR14 is expressed as a 4.2kb transcript predominantly in adult liver and at late stages of foetal development. The WBSCR14 locus encompasses 33 kb of genomic DNA with 17 exons. Two intragenic polymorphic dinucleotide repeats have been identified and used to verify hemizygosity in WBS patients. We have also cloned the mouse ortholog and mapped its locus to mouse chromosome 5, in a region of conserved synteny with human 7q11.23. Given that other bHLHZip proteins are dosage sensitive and based on the putative function of WBSCR14 as a transcription factor, hemizygosity at this locus could be involved in some features of WBS. Show less