Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions.

OBJECTIVE: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized. METHOD: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings. RESULTS: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period. CONCLUSION: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management.

Combined Genome Sequencing and RNA Analysis Reveals and Characterizes a Deep Intronic Variant in IGHMBP2 in a Patient With Spinal Muscular Atrophy With Respiratory Distress Type 1.

BACKGROUND: Pathogenic variants in the IGHMBP2 gene cause recessive spinal motor neuropathies of variable phenotype, including a predominantly distal motor impairment of Charcot-Marie-Tooth type 2S and the more severe condition of spinal muscular atrophy with respiratory distress type 1 in which infantile respiratory failure predominates. METHODS: We describe the first reported case of spinal muscular atrophy with respiratory distress type 1 caused by a novel deep intronic variant in IGHMBP2 (NM_002180c.712-610A>G). RESULTS: The variant was detected by whole genome sequencing. Reverse transcription-polymerase chain reaction and complimentary DNA sequencing were used to characterize the impact of the novel variant. CONCLUSIONS: This report illustrates the utility in clinical practice of genome sequencing and RNA analysis, compared with exome sequencing alone.

Acute leukemia in a patient with 15q overgrowth syndrome.

Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34-year-old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem-cell transplant.

ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis.

PURPOSE: Diagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to explain the patient's phenotypes. To use these tools, busy clinicians must manually encode patient phenotypes from lengthy clinical notes. With 100 million human genomes estimated to be sequenced by 2025, a fast alternative to manual phenotype extraction from clinical notes will become necessary. METHODS: We introduce ClinPhen, a fast, high-accuracy tool that automatically converts clinical notes into a prioritized list of patient phenotypes using Human Phenotype Ontology (HPO) terms. RESULTS: ClinPhen shows superior accuracy and 20× speedup over existing phenotype extractors, and its novel phenotype prioritization scheme improves the performance of gene-ranking tools. CONCLUSION: While a dedicated clinician can process 200 patient records in a 40-hour workweek, ClinPhen does the same in 10 minutes. Compared with manual phenotype extraction, ClinPhen saves an additional 3-5 hours per Mendelian disease diagnosis. Providers can now add ClinPhen's output to each summary note attached to a filled testing laboratory request form. ClinPhen makes a substantial contribution to improvements in efficiency critically needed to meet the surging demand for clinical diagnostic sequencing.

Yield of head CT in the alcohol-intoxicated patient in the emergency department.

We aimed to determine the yield of positive head computed tomography (CT) findings among suspected alcohol-intoxicated patients presenting to the emergency department (ED). Our secondary aim was to determine if elderly intoxicated patients were more likely to have an intracranial injury. We identified patients suspected of alcohol intoxication who underwent CT scanning in the ED over a 4-year period. Pre-determined data elements including demographics, diagnosis, and disposition were extracted using a pre-formatted data sheet by blinded abstractors. "Positive" CT was defined as evidence of any type of intracranial hemorrhage. A total of 2,671 subjects with suspected alcohol intoxication and a head CT were identified. Fifty out of the 2,671 (1.9%) had a positive CT. Among CT scans of elderly (≥60 years of age) subjects, 15/555 (2.7%, 95% CI = 1.4-4.1%) were positive compared with 35/2,116 (1.7%, 95% CI = 1.1-2.2%) among those <60 years of age (p = 0.11). The yield of positive head CT among alcohol-intoxicated patients was low, at 1.9%. An age cutoff of 60 years in this population did not predict a significantly higher positive rate.

Epidemiology of nontuberculous mycobacteria in patients without HIV infection, New York City.

We reviewed medical records of patients without known HIV and with positive cultures for nontuberculous mycobacteria (NTM) isolated during 2000-2003 from 1 large hospital in New York, New York. Overall, 505 patients had positive NTM cultures; 119 (24%) met the criteria for NTM disease. The difference between demographic characteristics of case-patients in our study (66% female, 61% white, and 59% > 60 years of age) and those of the base population as determined by regional census data was statistically significant. Estimated incidences for positive cultures, all disease, and respiratory tract disease were 17.7, 2.7, and 2.0 per 100,000 persons, respectively. More patients with rapidly growing mycobacteria (61%), Mycobacterium kansasii (70%), or M. marinum (100%) met criteria for disease than did patients with M. avium complex (MAC) (27%, (p < 0.01). NTM disease in patients without HIV is increasing. Laboratory-based surveillance may be useful for detecting non-MAC and non-respiratory tract disease.

Cancer screening practices of Asian American physicians in New York City.

Cancer screening rates are lower among Asian Americans than the general USA population. While prior studies examined characteristics of Asian American patients as predictors of cancer screening, few investigated their health care providers. Asian American primary care physicians practicing in New York City were surveyed by questionnaire regarding their demographics, practice characteristics, and cancer screening of their Asian American patients. Of the 117 eligible respondents, 96% recommended mammograms to their Asian patients 50+ years of age and 70% to patients 40-49-year-old. Only 30% of respondents use both age and onset of sexual activity to determine when to recommend Pap smears. For colorectal cancer screening, the rates of performing fecal occult blood testing or recommending colonoscopy or sigmoidoscopy were 77% and 74%. About 70% recommend screening for hepatitis B. Gender and ethnicity of the physician were found to be significant predictors for cancer screening practice.

Screening for vancomycin-resistant enterococci using stools sent for Clostridium difficile cytotoxin assay is effective: results of a survey of 300 Patients in a large Singapore Teaching Hospital.

INTRODUCTION: To assess the efficacy of screening stools sent for Clostridium difficile cytotoxin assay (CDTA) for surveillance of vancomycin-resistant enterococci (VRE). MATERIALS AND METHODS: From April to May 2005, all stools submitted for CDTA were also cultured for VRE using vancomycin containing culture media. Isolates were identified to species level and vancomycin resistance confirmed, followed by polymerase chain reaction (PCR) for detection of vancomycin resistance genes and DNA fingerprinting. Over 2 consecutive days during that period, stool specimens or rectal swabs were also obtained from all patients in high-risk units (haematology, oncology, renal and intensive care). Fifty-one patients in each group were compared in terms of VRE risk factors previously identified. RESULTS AND DISCUSSION: The prevalence of VRE in both groups was similar [3/204 (1.5%) in the CDTA arm and 1/97 (1.0%) in the high-risk arm; P = 1.0, Fisher's exact test]. Prevalence of risk factors for VRE colonisation, including age, duration of hospitalisation, exposure to antibiotics, exposure to surgical procedures, presence of malignancy and diabetes mellitus was similar in both groups (P > 0.05). Only renal failure (P < 0.05) was more common in the high-risk group. All 4 isolates of VRE identified were genetically distinct by variable number tandem repeat (VNTR) typing; 3 were Enterococcus faecium (2 with the vanB gene, 1 with vanA) and one E. faecalis. CONCLUSION: Less than 2% of our high-risk patients are VRE carriers. In-hospital VRE screening using stools sent for CDTA is a simple, reasonable surrogate for screening individual high-risk patients as the patient risk profile is similar and the yield comparable in a low-prevalence setting.