Detection of Clinically Relevant Monogenic Copy-Number Variants by a Comprehensive Genome-Wide Microarray with Exonic Coverage.

Background: Disease-causing copy-number variants (CNVs) often encompass contiguous genes and can be detected using chromosomal microarray analysis (CMA). Conversely, CNVs affecting single disease-causing genes have historically been challenging to detect due to their small sizes.

Methods: A custom comprehensive CMA (Baylor College of Medicine - BCM v11.

Leveraging the T2T assembly to resolve rare and pathogenic inversions in reference genome gaps.

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) ( = 9) or srGS ( = 3) and resolve nine of them.

Brain abscesses, neutropenia, and B-ALL: Multiple testing modalities required to confirm PDCD10 and ETV6 dual diagnoses.

Recognition of patients with multiple diagnoses, and the unique challenges they pose to clinicians and laboratorians, is increasing rapidly as genome-wide genetic testing grows in prevalence. We describe a unique patient with dual diagnoses of PDCD10-related cerebral cavernous malformations and ETV6-related thrombocytopenia with associated neutropenia. She presented with brain abscesses as an infant, which is highly atypical for these disorders in isolation.

NODAL variants are associated with a continuum of laterality defects from simple D-transposition of the great arteries to heterotaxy.

Background: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.

RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.

Compound heterozygosity of a de novo submicroscopic deletion and an inherited frameshift pathogenic variant in the gene in a fetus with bilaterally enlarged and echogenic kidneys, enlarged abdomen and oligohydramnios.

We present a fetus with bilaterally enlarged and echogenic kidneys. Prenatal testing detected compound heterozygosity for a 0.676 Mb de novo deletion and an inherited pathogenic variant in .

Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA).

TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.

The multiple de novo copy number variant (MdnCNV) phenomenon presents with peri-zygotic DNA mutational signatures and multilocus pathogenic variation.

Background: The multiple de novo copy number variant (MdnCNV) phenotype is described by having four or more constitutional de novo CNVs (dnCNVs) arising independently throughout the human genome within one generation. It is a rare peri-zygotic mutational event, previously reported to be seen once in every 12,000 individuals referred for genome-wide chromosomal microarray analysis due to congenital abnormalities. These rare families provide a unique opportunity to understand the genetic factors of peri-zygotic genome instability and the impact of dnCNV on human diseases.

Sequencing individual genomes with recurrent genomic disorder deletions: an approach to characterize genes for autosomal recessive rare disease traits.

Background: In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics.

Methods: We constructed a genome-wide map for nonallelic homologous recombination (NAHR)-mediated recurrent genomic deletions and used this map to estimate population frequencies of NAHR deletions based on large-scale population cohorts and region-specific studies. We calculated recessive disease carrier burden using high-quality pathogenic or likely pathogenic variants from ClinVar and gnomAD.

Recurring germline mosaicism in a family due to reversion of an inherited derivative chromosome 8 from an 8;21 translocation with interstitial telomeric sequences.

Background: Mosaicism for chromosomal structural abnormalities, other than marker or ring chromosomes, is rarely inherited.

Methods: We performed cytogenetics studies and breakpoint analyses on a family with transmission of mosaicism for a derivative chromosome 8 (der(8)), resulting from an unbalanced translocation between the long arms of chromosomes 8 and 21 over three generations.

Results: The proband and his maternal half-sister had mosaicism for a der(8) cell line leading to trisomy of the distal 21q, and both had Down syndrome phenotypic features.

Clinical exome sequencing uncovers a high frequency of Mendelian disorders in infants with stroke: A retrospective analysis.

Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1%-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke.

LMOD2-related dilated cardiomyopathy presenting in late infancy.

Leiomodin-2 (LMOD2) is an important regulator of the thin filament length, known to promote elongation of actin through polymerization at pointed ends. Mice with Lmod2 deficiency die around 3 weeks of age due to severe dilated cardiomyopathy (DCM), resulting from decreased heart contractility due to shorter thin filaments. To date, there have been three infants from two families reported with biallelic variants in LMOD2, presenting with perinatal onset DCM.

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

Purpose: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.

Methods: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex.

Contribution of uniparental disomy in a clinical trio exome cohort of 2675 patients.

Background: Uniparental disomy (UPD) is the inheritance of two homologous chromosomes from the same parent. UPD may result in clinical phenotypes when occurring on chromosomes with specific imprinting pattern, when leading to homozygosity of a deleterious recessive allele inherited from one carrier parent, or when associated with a mosaic aneuploidy. Due to the importance of UPD in genetic disease etiology, UPD analysis has started to be implemented in the context of exome sequencing (ES) or genome sequencing.

A rare description of pure partial trisomy of 16q12.2q24.3 and review of the literature.

Trisomy 16 is the most common autosomal trisomy in humans, which is almost uniformly embryonic lethal. Partial trisomy 16 including a segment of the long arm of chromosome 16 is occasionally compatible with life and has been associated with severe congenital defects, growth retardation, and early lethality. Segmental trisomy of 16q is usually described concomitantly with partial monosomy of another chromosome, often resulting from a parental balanced translocation.

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes.