Novel variants in the SOX11 gene: clinical description of seven new patients.

Pathogenic SOX11 variants have been associated with intellectual developmental disorder with microcephaly, and with or without ocular malformations or hypogonadotropic hypogonadism (HH) (IDDMOH, OMIM # 615866). In this article, we report seven new patients with de novo SOX11 variants. Five of the variants are missense, one nonsense, and one whole-gene deletion, most of them are novel variants.

Innovative all-in-one exome sequencing strategy for diagnostic genetic testing in male infertility: Validation and 10-month experience.

Background: Current guidelines indicate that patients with extreme oligozoospermia or azoospermia should be tested for chromosomal imbalances, azoospermia factor (AZF) deletions and/or CFTR variants. For other sperm abnormalities, no genetic diagnostics are recommended.

Objectives: To determine whether exome sequencing (ES) with combined copy number variant (CNV) and single nucleotide variant (SNV) analysis is a reliable first-tier method to replace current methods (validation study), and to evaluate the diagnostic yield after 10 months of implementation (evaluation study).

Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery.

De novo heterozygous missense variants in as cause of fetal pleural effusions and progressive fetal hydrops.

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom heterozygous missense variants in the planar cell polarity gene were detected using exome sequencing. Using several in vitro assays, we show that the p.

A Novel Distal 22Q11.21 Microduplication in a 43-Year-Old Male Patient with Mild Intellectual Disability, Social Cognitive Dysfunctions, and Anxiety.

Objective: The chromosome region 22q11.2 is highly susceptible to genomic rearrangements. It has become clear that genomic instability extends distally to the commonly deleted/duplicated region (Low Copy Repeats [LCR] A-D) and that a clear difference exists between the phenotypic presentation of patients with rearrangements in the common region versus that in the distal region (LCR D-H), particularly with respect to developmental and somatic issues.

Genetic diagnostic approach to intellectual disability and multiple congenital anomalies in Indonesia.

Intellectual disability (ID) and multiple congenital anomalies (MCA) are major contributors to infant mortality, childhood morbidity, and long-term disability, with multifactorial aetiology including genetics. We aim to set a diagnostic approach for genetic evaluation of patients with ID and MCA, which can be applied efficiently with a good diagnostic rate in Indonesia or other low resources settings. Out of 131 ID cases, twenty-three individuals with ID/global developmental delay (GDD) and MCA were selected from two-steps of dysmorphology screening and evaluation.

A complex structural variant near causes X-linked split-hand/foot malformation.

Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci.

Copy number variants from 4800 exomes contribute to ~7% of genetic diagnoses in movement disorders, muscle disorders and neuropathies.

Various groups of neurological disorders, including movement disorders and neuromuscular diseases, are clinically and genetically heterogeneous. Diagnostic panel-based exome sequencing is a routine test for these disorders. Despite the success rates of exome sequencing, it results in the detection of causative sequence variants in 'only' 25-30% of cases.

All-in-one whole exome sequencing strategy with simultaneous copy number variant, single nucleotide variant and absence-of-heterozygosity analysis in fetuses with structural ultrasound anomalies: A 1-year experience.

Objective: We performed a 1-year evaluation of a novel strategy of simultaneously analyzing single nucleotide variants (SNVs), copy number variants (CNVs) and copy-number-neutral Absence-of-Heterozygosity from Whole Exome Sequencing (WES) data for prenatal diagnosis of fetuses with ultrasound (US) anomalies and a non-causative QF-PCR result.

Methods: After invasive diagnostics, whole exome parent-offspring trio-sequencing with exome-wide CNV analysis was performed in pregnancies with fetal US anomalies and a non-causative QF-PCR result (WES-CNV). On request, additional SNV-analysis, restricted to (the) requested gene panel(s) only (with the option of whole exome SNV-analysis afterward) was performed simultaneously (WES-CNV/SNV) or as rapid SNV-re-analysis, following a normal CNV analysis.

Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review.

The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis.

The performance of genome sequencing as a first-tier test for neurodevelopmental disorders.

Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios.

Phenotype of COL3A1/COL5A2 deletion patients.

Introduction: The diagnosis of Ehlers-Danlos syndrome is usually based on well-defined diagnostic criteria and the result of DNA investigation. Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1. We describe 3 cases with contiguous deletions resulting in haploinsufficiency of both genes with relative mild features of connective tissue disease.

Identification of a Novel Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency.

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in , resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous variant Chr8:NM_000498.3:c.

Recommendations for whole genome sequencing in diagnostics for rare diseases.

In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions.

Phenotype based prediction of exome sequencing outcome using machine learning for neurodevelopmental disorders.

Purpose: Although the introduction of exome sequencing (ES) has led to the diagnosis of a significant portion of patients with neurodevelopmental disorders (NDDs), the diagnostic yield in actual clinical practice has remained stable at approximately 30%. We hypothesized that improving the selection of patients to test on the basis of their phenotypic presentation will increase diagnostic yield and therefore reduce unnecessary genetic testing.

Methods: We tested 4 machine learning methods and developed PredWES from these: a statistical model predicting the probability of a positive ES result solely on the basis of the phenotype of the patient.