Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review
Abstract
Autosomal dominant variants in transcription factor 20 (TCF20) can result in TCF20-associated neurodevelopmental disorder (TAND), a condition characterized by developmental delay and intellectual disability, autism, dysmorphisms, dystonia, and variable other neurological features. To date, a total of 91 individuals with TAND have been reported; ~67% of cases arose de novo, while ~10% were inherited, and, intriguingly, ~8% were either confirmed or suspected to have arisen via germline mosaicism. Here, we describe two siblings with a developmental condition characterized by intellectual disability, autism, a circadian rhythm sleep disorder, and attention deficit hyperactivity disorder (ADHD) caused by a novel heterozygous single nucleotide deletion in the TCF20 gene, NM_001378418.1:c.4737del; NP_001365347.1:p.Lys1579Asnfs*36 (GRCh38/hg38). The variant was not detected in DNA extracted from peripheral blood in either parent by Sanger sequencing of PCR-generated amplicons, or by deep sequencing of PCR amplicons using MiSeq and MinION. However, droplet digital PCR (ddPCR) of DNA derived from early morning urine detected the variation in 3.2% of the father's urothelial cells, confirming germline mosaicism. This report is only the second to confirm with physical evidence TCF20 germline mosaicism and discusses germline mosaicism as a likely under-detected mode of inheritance in neurodevelopmental conditions.
How strong is the evidence?
Evidence Hub reads this as a case report, done in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health. Reported size: 91 participants or records.
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