WT1 complete gonadal dysgenesis with membranoproliferative glomerulonephritis: case series and literature review.

Background: Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome.

Methods: The clinical and genetic data from 3 individuals are reported.

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy).

Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases.

Lessons learnt from MDM2 fluorescence in-situ hybridisation analysis of 439 mature lipomatous lesions with an emphasis on atypical lipomatous tumour/well-differentiated liposarcoma lacking cytological atypia.

Aims: Amplification of the murine double minute-2 (MDM2) gene, which is usually detected with fluorescence in-situ hybridisation (FISH), is the key driving event for atypical lipomatous tumours (ALTs)/well-differentiated liposarcomas (WDLs). We sought to determine the concordance between the histopathological findings and MDM2 FISH in the diagnosis of ALT/WDL, and to identify the histological features of MDM2-amplified tumours lacking classic atypia.

Methods And Results: We performed a retrospective analysis of all mature lipomatous lesions subjected to MDM2 FISH analysis at our institution.

Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study.

Background: The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing.

Objective: This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities.

Reduced sensitivity for T790M mutations using the Idylla EGFR Mutation Test.

Aims: Osimertinib is a third-generation (epidermal growth factor receptor) tyrosine kinase inhibitor that is effective in non-small cell lung cancer (NSCLC) harbouring the T790M mutation. The Idylla EGFR Mutation Test is a rapid cartridge-based method for detecting T790M and other mutations. However, false negative T790M results have been reported, and the sensitivity of the assay for this mutation is uncertain.

Prevalence of the EGFR T790M and other resistance mutations in the Australian population and histopathological correlation in a small subset of cases.

We sought to review the prevalence of EGFR T790M and other EGFR mutations associated with either proven or probable tyrosine kinase inhibitor (TKI) resistance in the Australasian lung cancer population and to perform histopathological correlation in a subset of cases. Retrospective statistical analysis was performed on a set of targeted lung cancer gene mutation tests (FIND IT gene panel) performed at Sonic Healthcare during 2018 and early 2019. A total of 1833 lung adenocarcinoma tumour samples underwent somatic mutation testing.

A minimum estimate of the prevalence of 22q11 deletion syndrome and other chromosome abnormalities in a combined prenatal and postnatal cohort.

Study Question: What is the frequency of major chromosome abnormalities in a population-based diagnostic data set of genomic tests performed on miscarriage, fetal and infant samples in a state with >73 000 annual births?

Summary Answer: The overall frequency of major chromosome abnormalities in the entire cohort was 28.2% (2493/8826), with a significant decrease in the detection of major chromosome abnormalities with later developmental stage, from 50.9% to 21.

Association between timing of diagnosis of trisomy 21, 18, and 13 and maternal socio-economic status in Victoria, Australia: A population-based cohort study from 2015 to 2016.

Objectives: To explore the association between timing of diagnosis of common autosomal trisomies, maternal age, and socio-economic status (SES).

Design: Retrospective study of cytogenetic diagnoses of trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13) in Victoria, Australia, in 2015 to 2016, stratified by timing (prenatal less than 17 weeks gestation, prenatal including or greater than or 17 weeks gestation, and postnatal before 12 months of age), maternal age, and SES region. Utilisation of prenatal testing following a live-born T21 infant was ascertained via record linkage.

DNA extraction from placental, fetal and neonatal tissue at autopsy: what organ to sample for DNA in the genomic era?

Incorporation of genome and exome sequencing into fetal and neonatal autopsy investigations has been shown to improve diagnostic yield. This requires deoxyribonucleic acid (DNA) to be extracted from either the placenta or autopsy tissue for molecular testing. However, the sources and quality of DNA obtained are highly variable and there are no adequate published data on what tissue is most ideal to sample for DNA extraction in this setting.

Non-invasive prenatal testing.

Background: Non-invasive prenatal testing (NIPT), also known as cell-free DNA testing and non-invasive prenatal screening (NIPS), is an important addition to the range of screening tests for fetal chromosomal abnormalities. For trisomy 21 in particular, NIPT is superior to other screening modalities. However, NIPT has limitations and complexities that requesting clinicians and their patients should understand.

Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death.

Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype-genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death.

Isolated Ventricular Noncompaction Cardiomyopathy Presenting as Fetal Hydrops at 24 Weeks Gestation.

Ventricular noncompaction cardiomyopathy is a rare form of congenital cardiomyopathy with increasing evidence of genetic etiology, especially when presenting in childhood. Fetal presentation is rare. We describe a case of fetal hydrops, presenting at 24 weeks gestation and leading to intrapartum death at 26 weeks gestation.

Ovarian Microcystic Stromal Tumor: A Rare Clinical Manifestation of Familial Adenomatous Polyposis.

Microcystic stromal tumor (MST) is a rare tumor of presumed sex-cord stromal differentiation. We present a case of MST arising within a patient with constitutional 5q deletion syndrome, whose deletion encompassed the APC gene. Genomic analysis of the MST revealed a point mutation in the remaining APC allele, predicted to result in abnormal splicing of Exon 7.

Mosaic 22q11.2 deletion and tetralogy of Fallot with absent pulmonary valve: an unreported association.

Chromosome 22q11.2 microdeletion is the most common microdeletion syndrome. Mosaic 22q11.

Complete penoscrotal transposition: case report and review of the literature.

Penoscrotal transposition is a rare congenital abnormality. We report a case presenting prenatally with ambiguous genitalia and renal anomaly on obstetric ultrasound and fetal MRI and discuss the postnatal examination and autopsy findings. We present a review of the literature, including associated gene abnormalities.

KRAS mutation testing of metastatic colorectal cancer in Australia: where are we at?

Aim: To carry out a nationwide study of KRAS testing in metastatic colorectal cancer as reported by nine major molecular pathology service providers in Australia, including mutation frequencies and turnaround times that might impact on patient care.

Methods: Participating laboratories contributed information on KRAS mutation frequencies, including the G13D mutation type, as well as turnaround times for tumor block retrieval and testing.

Results: The KRAS mutation frequency observed by nine different test sites for a total of 3688 metastatic colorectal cancers ranged from 34.

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy.

We present a patient with a behavioral disorder, epilepsy, and autism spectrum disorder who has a 520 kb chromosomal deletion at 15q26.1 encompassing three genes: ST8SIA2, C15orf32, and FAM174B. Alpha-2,8-Sialyltransferase 2 (ST8SIA2) is expressed in the developing brain and appears to play an important role in neuronal migration, axon guidance and synaptic plasticity.