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
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).
