Xuyun Hu

Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia.

AIMS To characterize aspects of Nedd4L in prostate cancer (PC) by assessing its expression in hyperplastic and malignant prostate tissue, and to correlate findings with PC histologic grade. MATERIALS AND METHODS Radical prostatectomy (RP) specimens from 56 patients with clinically localized PC, and benign prostatic hyperplasia (BPH) transurethral resection specimens from 31 patients, were assessed for Nedd4L expression using immunohistochemistry. RESULTS Nedd4L (P<0.001) expressions were significantly decreased in PC compared to benign prostate tissue. Furthermore, downregulation of Nedd4L (P<0.05) expression correlated with increasing Gleason score. CONCLUSIONS These data suggest that prostate cancer cells in vivo may need Nedd4L expression to regulate TGF-beta1 signaling, and that Nedd4L expression might be involved in prostate cancer development.

Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience

PurposeTo evaluate the performance of proband-only medical exome sequencing (POMES) as a cost-effective first-tier diagnostic test for pediatric patients with unselected conditions.MethodsA total of 1,323 patients were tested by POMES, which targeted 2,742 known disease-causing genes. Clinical relevant variants were Sanger-confirmed in probands and parents. We assessed the diagnostic validity and clinical utility of POMES by means of a survey questionnaire.ResultsPOMES, ordered by 136 physicians, identified 512 pathogenic or likely pathogenic variants associated with over 200 conditions. The overall diagnostic rate was 28.8%, ranging from 10% in neonatal intensive care unit patients to over 35% in pediatric intensive care unit patients. The test results had an impact on the management of the 45.1% of patients for whom there were positive findings. The average turnaround time was 57 days; the cost was

Maternal uniparental disomy 14 and mosaic trisomy 14 in a Chinese boy with moderate to severe intellectual disability

360/case.ConclusionWe adopted a relatively efficient and cost-effective approach in China for the molecular diagnosis of pediatric patients with suspected genetic conditions. While training for clinical geneticists and other specialists is lagging behind in China POMES is serving as a diagnostic equalizer for patients who do not normally receive extensive clinical evaluation and clinical diagnosis prior to testing. This Chinese experience should be applicable to other developing countries that are lacking clinical, financial, and personnel resources.

de novo interstitial deletions at the 11q23.3-q24.2 region

BackgroundBoth maternal uniparental disomy 14 (UPD(14)mat) and mosaic trisomy 14 are rare events in live individuals. A combination of the two events in one individual is rarely encountered. Only six live-born cases have so far been reported.Case presentationHere we reported a case of concomitant UPD(14)mat and mosaic trisomy 14 in a 10-year-old Chinese patient. Most clinical features of our patient were consistent with those previous reported for UPD(14)mat cases, which include prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, truncal obesity, small hands and feet, short stature, and mild facial dysmorphism, but our patient showed more severe intellectual disability and no sign of precocious puberty. SNP array analysis revealed a mixture of chromosome 14 maternal isodisomy with heterodisomy and a low level trisomy mosaicism of whole chromsome 14 in blood and hyperpigmented skin samples, whereas only UPD(14)mat was detected in normal skin sample. Cytogenetic analysis identified one trisomy 14 cell in 100 metaphase of peripheral blood lymphocytes (47,XX, +14[1]/46,XX[99]).ConclusionsTo our knowledge, this is the first case of a patient with UPD(14)mat and mosaic trisomy 14 reported in a Chinese patient. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD(14)mat and mosaic trisomy 14.

Novel compound heterozygous variants in the LHCGR gene identified in a subject with Leydig cell hypoplasia type 1

BackgroundJacobsen syndrome (JBS) is a contiguous gene deletion syndrome involving 11q terminal deletion. Interstitial deletions at distal 11q are rare and their contributions to the clinical phenotype of JBS are unknown.Case presentationWe presented the chromosome microarray (CMA) data and the clinical features of two individuals carrying a non-overlapping de novo deletion each at the 11q23.3-q24.2 region in an effort to analyze the correlation between region of deletion at 11q and phenotype. Both deletions are likely pathogenic for patient’s condition. The deletion at 11q23.3q24.1 is associated with short stature, relative microcephaly, failure to thrive, hypotonia and sleeping disorder. The deletion at 11q24.2 involves HEPACAM and our patient’s clinical presentation (relative macrocephaly, abnormal MRI, mild developmental delay and seizure) is not inconsistent with Megalencephalic leukoencephalopathy with subcortical cysts 2B.ConclusionsOur finds support the notion that more than one critical region at 11q23.3-qter are responsible for the variable clinical presentation of JBS, thus JBS is a true contiguous gene deletion syndrome where multiple loci contributed to the clinical characteristics of JBS. Small interstitial deletions at 11q23.3-q24.2 and their associated unique features also suggest emerging novel genomic disorders.

Novel pathogenic RECQL4 variants in Chinese patients with Rothmund-Thomson syndrome

Abstract Background: Leydig cell hypoplasia (LCH) is a rare disease and one of the causes of male disorder of sexual differentiation (DSD). Inactivating mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene account for the underlying LCH pathogenicity. This study aimed to analyze the clinical presentation and diagnosis as well as highlight the molecular characteristics of a subject with LCH type 1. Case presentation: Clinical data were collected from the subject and analyzed. Next generation sequencing of the immediate family pedigree using peripheral blood genomic DNA was performed, and the relevant mutations were verified with Sanger sequencing. We describe the case of a 5-year-old patient with DSD, presenting with a lateral inguinal hernia accompanied by abnormal hormone tests. The genetic analysis revealed novel compound heterozygous variants in the LHCGR gene, including a splice site mutation (c.681-1 G>A) and a frameshift variant (c.1582_1585del ATAT, p.Ile528*). Conclusions: We identified novel compound heterozygous variants in the LHCGR gene, and expanded the genotype-phenotype correlation spectrum of LHCGR variants.

Further defining the critical genes for the 4q21 microdeletion disorder.

BACKGROUND Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder mainly characterized by cutaneous poikiloderma, sparse hair, short stature and skeletal defects. Deleterious mutations in the RecQ-like DNA helicase type 4 (RECQL4) gene have been detected in approximately two-thirds of RTS cases. METHODS Three Chinese patients from two unrelated families were enrolled for clinical evaluation. Targeted next-generation sequencing (NGS) using a custom panel consisting of 705 short-stature-related genes was performed for the probands. Variants detected by NGS were confirmed by Sanger sequencing and examined in family members. RESULTS The probands presented with characteristic features of severe growth delay, poikiloderma mostly on the face, buttocks and extremities, sparse or absent hair, eyelashes, and eyebrows, forearm reduction defects, small hands with hypoplasia of the middle phalanx (little finger) in one of the probands, epicanthus, hypertelorism, and dental abnormalities. In addition, novel auricle features and other rare facial features, including narrow palpebral fissure, depressed nasal bridge, and small chin were exhibited. Four novel RECQL4 variants were identified, including three pathogenic frameshift variants, c.1724_1725delAC, p.His575fs*7; c.2421dupT, p.Asp808*; c.1770_1807del, p.Pro591fs*2, and one likely pathogenic missense variant, c.691G>A, p.Gly231Ser. CONCLUSION Our study expands the mutational spectrum of RECQL4 gene and reveals novel phenotypes observed in Chinese RTS patients.

A rare occurrence of two large de novo duplications on 1q42-q44 and 9q21.12-q21.33

4q21 microdeletion syndrome (MIM: 613509) is a new genomic disorder characterized by intellectual disability, absent or severely delayed speech, growth retardation, hypotonia, variable brain malformation, and facial dysmorphism. The critical genes had been proposed based on an overlapping 1.37 Mb genomic region. No further refinement has been done since year 2010. Here, we present three cases with 4q21 deletion identified by clinical chromosomal microarray analysis. One of the cases have a de novo 761 kb deletion which is the smallest deletion ever reported at this locus. It provides an opportunity to further define the critical regions/genes associated with specific features of the 4q21 microdeletion syndrome. The evidence support the notion that PRKG2 and RASGEF1B are critical genes for intellectual disability and speech defect, and the heterogeneous nuclear ribonucleoprotein HNRNPD and HNRNPDL (previously known as HNRPDL) genes are associated with growth retardation and hypotonia.

Novel pathogenic ACAN variants in non-syndromic short stature patients

De novo partial distal 1q trisomy is uncommon and mostly occurs in combination with monosomy of another chromosome due to a parental translocation. Distal 1q trisomy co-occurring with another de novo duplication on a separate chromosome is extremely rare. Here, we reported a patient carrying two large de novo interstitial duplications including a 20Mb duplication at 1q42-q44 and a 14.2Mb duplication at 9q21.12-q21.33. The patient presented with features of pre- and postnatal growth retardation, low birth weight, failure to thrive, developmental delay and frequent infection. Her dysmorphic features included macrocephaly, prominent forehead, triangular face, wide fontanelle, hypertelorism, flat nasal bridge, tented mouth, micrognathia, protruding and low-set ears, slender limbs with toe-walking appearance. In addition, she presented with subdural hematoma. The clinical presentations of this patient are mostly consistent with those of distal 1q trisomy syndrome or 9q interstitial duplication. The interstitial 1q trisomy may have contributed to the macrocephaly, prominent forehead and limb abnormalities of our patient. Either or both de novo duplications could have contributed to the features of growth retardation, developmental delay and dysmorphic features including hypertelorism, low-set ears and abnormal nose/nasal bridge.