Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies.

Objective: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).

Methods: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).

Results: Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity.

Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics.

Background: Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.

Methods: We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome.

Gene selection for the Australian Reproductive Genetic Carrier Screening Project ("Mackenzie's Mission").

Reproductive genetic carrier screening aims to offer couples information about their chance of having children with certain autosomal recessive and X-linked genetic conditions. We developed a gene list for use in "Mackenzie's Mission", a research project in which 10,000 couples will undergo screening. Criteria for selecting genes were: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child; and/or be one for which early diagnosis and intervention would substantially change outcome.

Pathogenic variants in result in a Stickler syndrome-like connective tissue disorder with vascular complications.

Background: Pathogenic variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of -related disease.

Methods: Reported phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous c.

User Acceptability of Whole Exome Reproductive Carrier Testing for Consanguineous Couples in Australia.

The study aimed to explore with consanguineous couples in Australia the acceptability and perceived utility of whole exome reproductive carrier screening for autosomal recessive and X-linked recessive conditions. Semi-structured interviews with 21 consanguineous couples were conducted prior to the offer of screening. Interviews were coded, and thematic analysis was informed by an inductive approach.

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.

Background: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants.

Objectives: This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test.

Methods: WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband.

Beyond the panel: preconception screening in consanguineous couples using the TruSight One "clinical exome".

Purpose: To provide proof of concept by broadening preconception screening beyond targeted testing to inform reproductive risk in consanguineous couples.

Methods: Consanguineous couples were screened for autosomal recessive and X-linked disorders using the TruSight One panel of 4,813 genes associated with human disease.

Results: We recruited 22 couples, of whom 15 elected to have sequencing.

Atypical Skin Manifestations in -Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

Crouzon syndrome (CS) and Beare-Stevenson syndrome (BSS) are craniosynostosis syndromes caused by mutations in the fibroblast growth factor 2 () gene. CS is more common (1 in 60,000 live births) than BSS, where fewer than 20 individuals have been reported. The cardinal features of BSS are craniosynostosis, cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and a prominent umbilical stump.

NAD Deficiency, Congenital Malformations, and Niacin Supplementation.

Background: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients.

KBG syndrome: An Australian experience.

In 2011, heterozygous mutations in the ANKRD11 gene were identified in patients with KBG syndrome. Since then, 100 cases have been described with the expansion of the clinical phenotype. Here we present 18 KBG affected individuals from 13 unrelated families, 16 with pathogenic mutations in the ANKRD11 gene.

Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature.

Angelman syndrome (AS) is characterized by severe intellectual disability, limited, or absent speech and a generally happy demeanor. The four known etiological mechanisms; deletions, uniparental disomy, imprinting defects, and UBE3A mutation all affect expression of the UBE3A gene at 15q11-q13. An atypical phenotype is seen in individuals who are mosaic for a chromosome 15q11-q13 imprinting defect on the maternal allele.

Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth.

Background: Fetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual's DNA can now be analysed through "whole" exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these.

Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations.

SOX10 is a transcription factor with well-known functions in neural crest and oligodendrocyte development. Mutations in SOX10 were first associated with Waardenburg-Hirschsprung disease (WS4; deafness, pigmentation defects and intestinal aganglionosis). However, variable phenotypes that extend beyond the WS4 definition are now reported.

Novel (ovario) leukodystrophy related to AARS2 mutations.

Objectives: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype.

Methods: Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected.

Mouse model implicates GNB3 duplication in a childhood obesity syndrome.

Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity.

Complex phenotypes in the haemoglobinopathies: recommendations on screening and DNA testing.

This document considers a number of scenarios involving complex haemoglobinopathies and provides 28 recommendations at both the clinical and laboratory levels on how these should be managed.

The Genetic Counseling Workplace-An Australasian Perspective. A National Study of Workplace Issues for Genetic Counselors and Associate Genetic Counselors.

Genetic counseling in Australasia (Australia and New Zealand) has been recognized as a profession since the 1980s and has steadily expanded over the past 20 years. The demography of major cities with metropolitan sprawl and sparsely populated rural areas has led to the establishment of 3 types of genetics units: main units in cities, metropolitan outreach, and rural outreach units. A questionnaire was developed to obtain information about the needs, resources, and day-to-day operation of the genetic counselors.