Page 69 - Read Online

Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32 Page 276

CATCH-22 syndrome
In 1993, based on studies of 44 subjects with the above-described clinical features, Wilson et al. proposed
the acronym of CATCH-22 (Cardiac disease, Abnormal facies, Thymic hypoplasia, Cleft palate, and
Hypocalcemia resulting from 22q11 deletions) . Prior to our understanding of the mechanisms of 22q11.2
[10]
microdeletion and CHARGE syndrome, these two conditions with overlapping clinical features were
included in CATCH-22 syndrome. These two syndromes often present with overlapping neuropsychiatric
features of ASD and will be discussed in this section.

(1) 22q11.2 microdeletion syndrome

The frequency of DiGeorge syndrome (DGS) is reported to be 1 in 3,000 to 1 in 6,000, making DGS one of
[11]
the most common chromosomal microdeletion syndromes . However, its clinical manifestations are
[12]
markedly variable, affected by a range of genetic and environmental modifiers . The degree of thymic
hypoplasia varies considerably from aplasia of a thymus, which presents as the complete absence of T cells,
to partial or almost intact thymus. The only curative measure for complete DGS is thymic transplant .
[11]
Partial defect of the thymus may be compensated by oligoclonal expansion of T cells in the later years, as
shown in the improvement in responses to vaccinations with age. However, oligoclonal expansion is
[11]
associated with a decrease in T cell diversity that may increase the risk of autoimmune complications .
Some DGS patients with partial thymic hypoplasia may present with predominant features of
developmental delay and neurocognitive and psychiatric disorders, making DGS diagnosis challenging to
clinicians. We have experienced a few DGS patients who were initially diagnosed with ASD and later found
to have the 22q11.2 microdeletion through chromosome microarray analysis. 22q11.2 region contains a
cluster of low copy repeats (LCRs) that mediate meiotic non-allelic homologous recombination between
LCRs and are susceptible to deletion or duplication . This region also codes long non-coding RNAs
[12]
[12]
(lncRNAs) and miRNAs that affect gene expression . Which part of this region is deleted also affects the
clinical features of DGS . For example, deletion of TBX1, which is essential for normal thymus formation,
[12]
leads to thymic aplasia or hypoplasia, greatly affecting T cell immunity, but not all DGS patients have
deletion of TBX1 [11,12] . Low T cell numbers may be detected by newborn screening (NBS) of T lymphopenia.
However, many DGS patients with mild to moderate T lymphopenia will be missed. When thymus
formation is impaired but not completely absent, T cell tolerance is affected partly due to decreased
expression of AIRE (autoimmune regulator), and reduced generation of central regulatory T cells . In
[13]
older patients, the development of autoimmune complications may also cause puzzling clinical features.
Apart from the TBX1 gene, this 22q11.2 region contains genes coding proteins that affect mitochondrial
[14]
metabolism, such as DGCR8 and TXNRD2 . Deletion of these genes leads to an increase in the production
of reactive oxygen species (ROS), further affecting immune functions and neuronal development. Deletion
of these genes is thought to contribute to impaired morphogenesis of the CNS and neuronal functioning in
DGS patients [14,15] . The deleted lesion of 22q11.2 also contains genes implicated with the pathogenesis of
schizophrenia or other neurodevelopmental conditions. For example, COMT hemizygosity and the
resultant reduction of enzymatic activity of COMT (catechol-o-methyltransferase) are implicated with
psychosis risk in 22q11.2 deletion syndrome and ASD-like psychiatric phenotypes . It was proposed that
[17]
[16]
the 22q11.2 microdeletion syndrome is a genetic model of neurodevelopmental phenotypes . The 22q11.2
[15]
microdeletion is easily detectable with the use of chromosomal microarray analysis; thus, clinicians seeing
ASD subjects must keep this syndrome in the differential diagnoses when ASD subjects present with clinical
symptoms indicating DGS.