ABSTRACT
BACKGROUND: Chromosomal microarray analysis (CMA) is recommended as the first-tier clinical diagnostic test for individuals with developmental disabilities. In addition to detecting copy number variations, CMA platforms with single nucleotide polymorphism probes can detect large homozygous regions within the genome, which represent potential risk for recessively inherited disorders. METHODS: To determine the frequency in which pathogenic or likely pathogenic variants can be detected in these regions of homozygosity, we performed whole exome sequencing (WES) in 53 individuals where homozygosity was detected by CMA. These patients were referred to our clinical laboratory for a variety of neurodevelopmental conditions including autism spectrum disorder, developmental delay, epilepsy, intellectual disability and microcephaly. RESULTS: In 11.3% (6/53) of cases, the analysis of homozygous variants revealed pathogenic or likely pathogenic variants in GJB2, TPP1, SLC25A15, TYR, PCCB, and NDUFV2 which are implicated in a variety of diseases. The evaluation of heterozygous variants with autosomal dominant inheritance, compound heterozygotes and variants with X-linked inheritance revealed pathogenic or likely pathogenic variants in PNPLA4, CADM1, HBB, SOS1, SFTPC, OTC and ASMT in 15.1% (8/53) of cases. Two of these patients harbored both homozygous and heterozygous variants relevant to their phenotypes (TPP1 and OTC; GJB2 and ASMT). CONCLUSIONS: Our study highlights the clinical utility of WES in individuals whose CMA uncovers homozygosity. Importantly, we show that when the phenotype is complex and homozygosity levels are high, WES can identify a significant number of relevant variants that explain neurodevelopmental phenotypes, and these mutations may lie outside of the regions of homozygosity, suggesting that the appropriate follow up test is WES rather than targeted sequencing.
Subject(s)
Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Exome Sequencing , Adolescent , Amino Acid Transport Systems, Basic/genetics , Aminopeptidases/genetics , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/genetics , Child , Child, Preschool , Cohort Studies , DNA Copy Number Variations , Diagnostic Tests, Routine , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Female , Homozygote , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , Microarray Analysis , Mitochondrial Membrane Transport Proteins , NADH Dehydrogenase/genetics , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Phenotype , Polymorphism, Single Nucleotide , Potassium Channels, Voltage-Gated/genetics , Sequence Analysis, DNA , Serine Proteases/genetics , Shaker Superfamily of Potassium Channels , Tripeptidyl-Peptidase 1 , Young AdultABSTRACT
Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.
Subject(s)
Karyotyping/methods , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/genetics , Oligonucleotide Array Sequence Analysis/methods , Adolescent , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/genetics , Child , Child, Preschool , Chromosome Aberrations , Chromosomes , Chromosomes, Human , Clinical Laboratory Techniques , Cohort Studies , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Female , Gene Dosage , Genetic Variation , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Male , Young AdultABSTRACT
We report the results of cytogenetic analysis of a case of unicameral bone cyst with a t(16;20(p11.2;q13) present as the sole abnormality. To our knowledge, this is only the second report of a cytogenetically characterized tumor of this type.
Subject(s)
Bone Cysts/genetics , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 20/genetics , Translocation, Genetic/genetics , Bone Cysts/pathology , Child , Humans , MaleABSTRACT
Hepatoblastoma is a rare embryonal malignancy of children. Trisomies or gains of chromosomes 1q, 2, 8, and 20 and a der(4)t(1;4)(q12;q34) have been described in hepatoblastoma. Herein, we describe a stage I fetal-type hepatoblastoma associated with a del(3)(q11.2q13.2).
