Balkan Journal of Medical Genetics

NOVEL DGAT1 MUTATIONS IDENTIFIED IN CONGENITAL DIARRHEAL DISORDER 7: A CASE REPORT WITH THERAPEUTIC EXPERIENCE
Shi C, Liu XL, Li XN, Zhao YJ
*Corresponding Author: Yunjing Zhao, PhD, Department of Pediatrics, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Shenyang 110004, China; Email: zhaoyunjing@sj-hospital.org
page: 69

CASE REPORT

A girl aged 3 months was admitted with the main complaint of slow weight gain. She was born by vaginal delivery without complications at 40 weeks’ gestation. The birth weight was 2.75 kg (weight for age: -1.13 SDS), and the birth length was 49.0 cm (length for age: -0.05 SDS). Her parents were not consanguineous and denied any familial history of genetic diseases. She was the first child of her parents. She had mixed feeding (breastfed and regular formal) and she presented watery diarrhea (twice a day) 2 days after birth, accompanied by occa- sional vomiting and slow weight gain. At 3 months, her height was 53.0 cm (length for age: -3.24 SDS). She was underweight and emaciated with the weight of 2.8 kg (weight for age: -5.0 SDS; weight for length: -4.0 SDS). The stool routine indicated increased fat globules without red or white blood cells. The serum 25-hydroxyvitamin D was as low as 3.29 ng/mL (normal range: 20-40 ng/mL). Both albumin (25.0 g/L, normal range: 35-53 g/L) and prealbumin (0.107 g/L, normal range: 0.18-0.45 g/L) were significantly reduced. The levels of serum potas- sium (3.48 mmol/L, normal range: 3.5-5.5 mmol/L) and sodium (130 mmol/L, normal range: 136-145 mmol/L) were slightly low. Aspartate aminotransferase was el- evated (60 U/L, normal range: 5-34 U/L). Blood sugar, hemoglobin, and plasma amino acids were within the normal ranges. The urine routine and urinary organic acids tests were also normal. She was diagnosed with se- vere malnutrition and hospitalization was recommended, which was not accepted by the parents. Take-home high- energy formula was thus provided to improve nutrition. However, the diarrhea worsened rapidly after 2 days of Nutricia formula feeding (5-6 times per day), and she was admitted to the Intensive Care Unit (ICU) for dehydra- tion and low serum bicarbonate (13.6 mmol/L, normal range: 22-28 mmol/L) ten days later. The stool routine was normal, and the virus and bacterial pathogens were negative. Immunoglobulin G was significantly decreased (IgG 0.99 g/L, normal range: 5.19-10.79 g/L), and lym- phocyte subset analysis was normal. Ultrasonography showed gallbladder stones. During that hospitalization, she received albumin, intravenous immunoglobulin infu- sions, red blood cell transfusion, and parenteral nutrition. Treatment with extensively hydrolyzed formula was ef- fective with no more diarrhea. She was discharged from the hospital after 20 days. Due to the unknown etiology of diarrhea and slow weight gain, a whole exome sequencing (WES) was performed using peripheral blood samples from the proband after obtaining written informed consent from the parents. Compound heterozygous mutations in DGAT1 were identified by WES and confirmed by Sanger se- quencing (Figure 1a, b): a paternally inherited variant of c.1215_1216delAG (p.Phe408fsTer74) and a maternally inherited variant of c.838C>T (p.Arg280*). Neither of the mutations has been reported in the human gene muta- tion database (HGMD), in the literature, nor found in the public or in-house databases. The variant of c.838C>T (p. Arg280*) was evaluated as “likely pathogenic” according to the American College of Medical Genetics and Genom- ics (ACMG) guidelines with evidence of PVS1+PM2. The variant of c.1215_1216 del AG (p.Phe408fsTer74) was evaluated as “pathogenic” according to the ACMG guideline with evidence of PVS1+PM2+PM3. No other variants in the WES data were found to be related to di- gestion and absorption. By reviewing the literature and disease database, a total of 26 DGAT1 variants (including ours) have been reported on in patients with CDD7. The schematic presentation of the DGAT1 mutation spectrum is depicted in Figure 2a. By constructing a three-dimen- sional molecular model, using Pymol software, these vari- ants caused an abnormal DGAT1 protein structure, which might be destructive for the normal function of protein (Figure 2b). The major clinical features of these patients are summarized in Table 1. The patient was referred to the developmental pedi- atrics for feeding guidance and physical monitoring since discharge. At first, an extensive hydrolyzed formula (a limited fat to 45.2% of total calories) was provided. There were no more complaints about diarrhea, yet there was also no weight gain observed for 2 months (Figure 3). She was recommended to consume a fat-restricted diet based on the definitive genetic diagnosis, with several explorations and modifications according to previous re- ports [1,3,5]. Treatment with adult low-fat milk powder (a limited fat of 3.6% of total calories) was subsequently chosen as an alternative. The consumption and ratio of milk powder and water was intensively calculated based on the weight and energy requirements. The patient’s growth parameters rapidly improved during regular follow-up (Figure 3). At of 15 months of age, her mal- nutrition was corrected with a catch-up with a weight of 9.7 kg (weight for age: +0.08 SDS, weight for length: +1.75 SDS). The short stature was slightly ameliorated (recumbent length 70.6 cm, length for age: -2.56 SDS). The absorptive parameters were satisfactory, with normal albumin and fat-soluble vitamin levels (Vitamin A, D, E, K). Triglycerides was also slightly elevated (1.7 mmol/L, normal range: 0.4-1.69 mmol/L). Our therapeutic experi- ence was supportive for early fat-restricted enteral diet in DGAT1-related CDD7.

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