👤 Lawrence C Layman

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare reproductive disorders with known genetic heterogeneity. Using exome sequencing, our group previously reported the prevalence of pathogenic and likely pathogenic (P/LP) variants in genes causing IHH/KS as the primary endpoint of our study. Here, we investigate the frequency of secondary findings (SF) to determine whether individuals with IHH/KS harbor an increased burden of P/LP variants in medically actionable genes (MAGs) defined by the American College of Medical Genetics and Genomics (ACMG). We analyzed exome sequencing data from 156 individuals with clinically confirmed IHH/KS. Variants were filtered for P/LP classification using ACMG guidelines across all 84 MAGs in ACMG SF v3.3. Sanger sequencing was used for orthogonal confirmation. The prevalence of MAG variants was compared to external control datasets from the U.K. Biobank (UKB, ~ 50,000 genomes) and the NIH eMERGE Network (~ 21,000 genomes), both based on the ACMG SF v2.0 59-gene list. Among 370,000 variants, 2 individuals (1.3%) carried validated P/LP variants in two distinct MAGs: SCN5A and MYBPC3. Genes 60-84, the additional 25 genes on the ACMG SF v3.3 list, yielded no additional variants. The prevalence of MAG variants in IHH/KS (1.3%) was not significantly different from UKB (2.0%) or eMERGE (2.5%) (OR vs. UKB: OR 0.64; 95% CI, 0.16-2.61; P = 0.57). The frequency of P/LP variants in MAGs among IHH/KS patients is comparable to the general population, suggesting that MAG variants are not common in IHH/KS in contrast to some other types of infertility. 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

Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. Cross-sectional study. University Research Laboratory. 158 patients with nHH/KS. Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. P/LP variants in nHH/KS genes. ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included. Show less

While chromosome 1 is the largest chromosome in the human genome, less than two dozen cases of interstitial microdeletions in the short arm have been documented. More than half of the 1p microdeletion cases were reported in the pre-microarray era and as a result, the proximal and distal boundaries containing the exact number of genes involved in the microdeletions have not been clearly defined. We revisited a previous case of a 10-year old female patient with a 1p32.1p32.3 microdeletion displaying syndromic intellectual disability. We performed microarray analysis as well as qPCR to define the proximal and distal deletion breakpoints and revised the karyotype from 1p32.1p32.3 to 1p31.3p32.2. The deleted chromosomal region contains at least 35 genes including NFIA. Comparative deletion mapping shows that this region can be dissected into five chromosomal segments containing at least six candidate genes (DAB1, HOOK1, NFIA, DOCK7, DNAJC6, and PDE4B) most likely responsible for syndromic intellectual disability, which was corroborated by their reduced transcript levels in RT-qPCR. Importantly, one patient with an intragenic microdeletion within NFIA and an additional patient with a balanced translocation disrupting NFIA display intellectual disability coupled with macrocephaly. We propose NFIA is responsible for intellectual disability coupled with macrocephaly, and microdeletions at 1p31.3p32.2 constitute a contiguous gene syndrome with several genes contributing to syndromic intellectual disability. Show less