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Page 277 Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32

(2) CHARGE syndrome

Impaired regulation of gene expression through chromatin remodeling affects numerous genes, resulting in
variable clinical manifestations involving multiple organs. CHARGE (coloboma, heart defect, atresia
choanae, retardation of growth and development, genital hypoplasia, and ear anomalies/deafness) syndrome
is one of such syndromes occurring 1:15,000 newborns and characterized by overlapping features of 22q11.2
[11]
microdeletion syndrome . Autosomal dominant pathogenic variants of CHD7 coding for the
chromodomain helicase DNA binding domain protein 7 (CHD7) cause this syndrome in up to 70% of
[11]
patients diagnosed with CHARGE syndrome . Effects of CHD7 on gene expression during neural crest
development may cause overlapping features of 22q11.2 microdeletion, including impaired thymic
[18]
development . Patients with CHARGE syndrome often initially present with marked hypotonia and
resultant severe gastroesophageal reflux disease (GERD) accompanied by impaired growth [11,19,20] . They often
require gastric tube feeding and Nissen fundoplication for controlling GERD. Developmental delay is also
highly prevalent, along with ASD-like behavioral symptoms in patients with CHARGE syndrome [21,22] .
Therefore, they are frequently diagnosed with ASD . Secondary to thymic hypoplasia, T cell anomalies
[21]
[23]
resembling those seen in DGS patients are also found at high frequency in CHARGE syndrome patients .
Clinicians are generally aware of feeding difficulty and developmental delay/behavioral symptoms in
patients with CHARGE syndrome. Aspects of possible immunodeficiency in CHARGE syndrome may be
overlooked. However, impaired T cell immunity and subsequent recurrent infection will further aggravate
behavioral symptoms in patients with CHARGE syndrome. An increase in autoimmune complications, as
seen in DGS patients, will also make clinical management challenging. Addressing a component of impaired
T cell immunity in CHARGE syndrome patients will be important for the best clinical outcomes.

Down syndrome (trisomy 21)
Down syndrome (DS) is the most common chromosomal abnormality, occurring in approximately 1:700
live births . DS patients are well known for their characteristic dysmorphism, developmental delay, and
[24]
other complications affecting multiple organs. DS patients present with ASD-like behavioral symptoms;
diagnosis of ASD in DS patients is reported to be 16%-41% . DS patients are also characterized by
[25]
abnormal thymic epithelium development, resulting in progressive thymic hypoplasia with age , and
[13]
further thymic abnormalities found in DGS patients. Their clinical features and progressive decline in
immune functions are mostly attributed to the presence of the 3rd chromosome 21. Excessive genes due to
trisomy 21 are associated with impaired regulation of redox state and a resultant increase in oxidative stress,
subsequently affecting the development of multiple organs . Such changes also contribute to premature
[26]
senescence and increased oxidative stress in thymus and other lymphoid organs, worsening progressively
with age [26,27] . As a result, in DS patients, impaired T cell immunity gets worse with age, often manifested as a
decline in antibody titers generated by childhood vaccinations: in infants or young DS children, DS patients
generally exhibit normal lymphocyte count and reveal decent responses to infant vaccines, but such
responses progressively get worse with age in some DS patients [27,28] . ikewise, cognitive functions may
decline with age in DS patients, indicating their need for more supportive measures for oxidative stress .
[14]
T cell depletion in DS patients is also partly attributed to hyperactivation of PI3K/AKT/mTOR pathways
due to gene dosage effects . Gene dosage effects also attenuate the activation of the NFAT (nuclear factor
[29]
of activated T cells) pathway, impairing signaling of TCR (T cell receptor)/NFAT signaling, which is also
important for brain functioning . Although genetic diagnosis of DS is relatively easy, clinical management
[30]
of DS patients, especially those with features of ASD, may be challenging. The contribution of immune
defects, which may not be evident at a young age, is likely to be overlooked, resulting in further worsening
of behavioral symptoms and oxidative stress due to recurrent infection. In DS patients in their 10s and 20s
with worsening behavioral symptoms and recurrent infection, a possible decline of humoral immunity may