The advent of the modern molecular genetic test such as the whole exome sequencing (WES) test has brought diagnostic accuracy and clarity to identify and rule out rare genetic diseases that present with remarkable clinical ambiguity [1],[2],[3]. This test has also proved its potentials to identify a misdiagnosis and project the course of diagnosis toward the definite genetic etiology [4]. Its higher diagnostic yield over the conventional genetic testing is making this test more relevant and effective for clinical diagnosis of various rare genetic conditions [5].

Now a 19-year-old adolescent male, who has been followed up in our clinic since he was a toddler, had presented at the age of two with high arched eyebrow, cleft palate, palpebral fissures, flattened nasal tip, imperforate anus, short stature and had undergone several corrective surgeries for his congenital deformities. Continued morbidity during childhood included chronic otitis leading to conductive hearing loss, elevated liver enzymes, and one episode hypoglycemia resulting in seizure.

Based on his clinical features including his facial dysmorphology (high arched eyebrow, palpebral fissures, flattened nasal tip) in association with his short stature, chronic otitis, conductive hearing loss, and the hypoglycemia leading to seizure led to diagnosis of Kabuki syndrome. Kabuki syndrome was first described in Japanese medical literature in 1981, characterized by multisystem disorders (commonly including facial features that resemble the Kabuki a theatre art form in Japan where the artists wear elaborated facial make-up to exaggerate expressions), growth delays, intellectual disability, and short stature. At the time of initial presentation, the advanced genetic testing for confirmation of this diagnosis was not available.

The molecular test now recently made available was performed to confirm the diagnosis of Kabuki syndrome, however it came negative for the genes KMT2D/MLL2 and KDM6A. This prompted evaluation looked for other rare genetic disorders.

As part of the panel of testing, WES for CDG was done as the clinical features were also somewhat suggestive of this pathology (Table 1). It showed genes defective for phosphomannomutase (PMM) enzyme, thus confirming a diagnosis of CDG, a genetic disorder with deficiency of enzymes needed for glycosylation of various proteins that ultimately causes formation of non-dysfunctional protein materials needed for numerous body functions.

Congenital disorder of glycosylation (Table 2) was first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues [6]. It is a broadly used term comprising of over 130 rare genetic disorder with defect in a subtle molecular process known as glycosylation. This process consists of formation of sugar chains and their attachment to the proteins and lipids, ultimately creating glycoprotein and glycolipid. These glycoprotein and glycolipid compounds perform various important functions in the body. As this process of glycosylation requires several enzymes to function, genetic defects leading to deficiency of these enzymes can significantly disrupt the process of glycosylation and give rise to various structural/physiological abnormalities [6].

Detail sequencing of a large portion of DNA can be done through WES testing. The complete set of genetic material is known as genome. The part of genome which is responsible for coding and protein synthesis is called exon. All these exons are called together as “Exome.” Whole exome sequencing testing is able to sequence and detect any defects in these exomes. Since most of the genetic mutations which lead to disease condition are present in exons, the WES testing is able to detect those, making it a very efficient method [7].

The first successful use of WES testing was to diagnose a rare form of inflammatory bowel disease in an infant [8]. In addition to diagnosing, WES testing can also find the causative mutation which can guide treatment plan, avoidance of expensive and invasive testing, and confirmed diagnoses, which are essential for eligibility for benefits and access to clinical trials [8]. A significant study has also suggested that, WES testing has increased causal variant detection and has a higher speed of diagnosis and lower cost compared with traditional diagnostic investigations in the study population, which suggest that WES testing should be done early in clinical settings with similar patient populations [9].

The diagnosis of our patient was clinically suggestive of Kabuki syndrome but was exposed to not be the case by molecular genetic testing that confirmed the diagnosis of congenital disorder of glycosylation (CDG) by whole exome sequencing (WES).