Applying the scoring scheme by Verloes, a patient can be assigned to atypical CHARGE syndrome, if they have one major criterion (choanal atreisia) and three minor criteria (heart malformation, deafness and external ear malformations) [
9]. Low set ears are not a typical feature of CHARGE syndrome. Abnormal outer ears always like cup-shaped in the typical CHARGE syndrome. The aetiology remains unknown. In the second screening of thyroid function (at the age of 1 mo), the patient was diagnosed with hypothyroidism. It has been reported that four patients had hypothyroidism combined with CHARGE syndrome: two had central hypothyroidism with a low response to the thyrotropin-releasing hormone loading test, while the others had primary hypothyroidism and received thyroxine replacement. Some cases also had Growth Hormone Deficiency (GHD) and used growth hormone therapy [
10]. This is a reason for the presentation of development delay and growth retardation. However, the concentration of growth hormone was not assessed in the neonatal period, and we could not determine the precise frequency of GHD in our patient. Typical features of CHARGE syndrome is well diagnosed, but the atypical part of the disease is difficult to identify. A person with subtle symptoms can pass their mutations on to offspring who is associated with a more severe phenotype. It is important to provide such patients with accurate prognostic information and genetic counseling. Additionally, compared to children or adults, features of CHARGE syndrome in neonates are atypical and less, so analysis of disease-associated genes including
CHD7 and
EFTUD2 should be done in infants, who do not completely meet the major clinical criteria. We identified a monoallelic c.4656dupT insertion of
CHD7, leading to a novel frameshift mutation and an early stop codon, which resulted in a truncated CHD7 protein.
CHD7 genomic structure spans 188 kb and consists of 38 exons, the first of which is noncoding.
CHD7 expression remains ubiquitous in later stages of fetal development. Problems appear early in the first trimester and specifically occur between the third and ninth weeks postconception [
12,
13]. At multiple stages of embryonic development indicate that CHD7 is localized to specific in both tissue and stage affected for CHARGE syndrome including the developing eye, ear and olfactory system [
4]. Sangar sequencing of CHD7 gene was used to detect mutations (point mutation, small deletions and/or insertions in exons) in infants who were suspected of CHARGE syndrome. However, the method may miss some cases. The technique of multiplex ligation dependent probe amplification was used as supplement to detect small exonic deletions. Studies showed that deficit in exon 7 of CHD7 gene was related to CHARGE syndrome [
11,
12]. Chai M found that
CHD7 is required for epigenetic activation of superenhancers and central nervous system-specific enhancers. Furthermore, they found that
CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate human neuroepithelial and central nervous system lineage identities [
14]. Okuno H found that the expression of genes associated with cell migration was altered in CHARGE iPSC-NCCs compared to control iPSC-NCCs. Their results support the historical inference that CHARGE syndrome patients exhibit defects in neural crest migration [
15]. Our case had a
CHD7 frameshift mutation at exon 20 leading to an early stop codonpredicting the loss of about 50% of the protein. Further studies are needed to delineate the roles of
CHD7 in enhancer-mediated transcriptional regulation in CHARGE syndrome in tissues of various development stages and their tissue expression sites. Genetic counseling was important for parents, even before we confirmed the diagnosis of CHARGE syndrome, because it could give them the information of the disease, realize the meaning of further genetic research, and provide the support to family. Most infants with CHARGE syndrome may develop abnormal, with motor and/or language problems, because of multiple sensory deficits. It is essential for family to early refer to rehabilitative therapist. Intelligence Quotients are various in the infants with CHARGE syndorme [
16]. In conclusion, we report a case of atypical CHARGE syndrome, with the clinical features of choanal atresia, a heart defect, and sensorineural deafness, caused by a novel frameshift mutation in exon 20 of
CHD7, with the new reading frame ending p. (Ile1553fs). Additional screening of atypical cases will be facilitated by molecular diagnosis. It should be emphasized that patients should not be rejected for
CHD7 analysis if they do not fulfill all the major criteria of CHARGE syndrome Verloes criteria.