The infant suffered from chronic renal function damage; this was first characterized by elevated serum levels of creatinine (Scr) since day 3 after birth, with an estimated glomerular filtration rate (eGFR) of 5.2 ml/min/1.73 m2. Gradually, the serum levels of Scr and blood urea nitrogen (BUN) exceeded standard levels. According to the Guidelines for Chronic Kidney Disease (CKD) in Children, he suffered from stage 5 CKD at birth, which then improved to stage 3 from 9 months (with eGFR 34.2 ml/min/1.73 m2) to 1.5 years (with eGFR 36.5 ml/min/1.73 m2). His liver function tests were abnormal, including increased total bilirubin (TBIL, 131.2 micromol/L; reference range: 5.4-22 micromol/L), direct bilirubin (DBIL, 22.2 micromol/L; reference range: 0.4-6.2 micromol/L), glutamyl transpeptidase (GGT, 598 U/L; reference range: 9-150 U/L), and alkaline phosphatase (ALP, 324 U/L; reference range: 20-281 U/L) on day 3 after birth. Elevated levels of alanine transaminase (ALT, 61 U/L; reference range: 0-41 U/L), aspartate aminotransferase (AST, 86 U/L; reference range: 0-38 U/L), total bile acid (TBA, 109 micromol/L; reference range: 0-12 micromol/L), and phosphorus (P, 3.22 mmol/L; reference range: 1.6-3.1 mmol/L) were evident when he was 1 month old. Elevated levels of triglycerides (TG, 2.21 mmol/L; reference range: 0.7-1.7 mmol/L) were evident when he was 3 months old. Elevated levels of cholesterol (CHoL, 8.88 mmol/L; reference range: <=5.17 mmol/L) were also evident at 6 months of age. The levels of TBIL and DBIL returned to normal 2 months after birth; however, other indicators continued to be abnormal. There was no metabolic acidosis. Additional testing included blood routine tests, TORCH, viral hepatitis tests, autoantibody tests, and plasma amino acids, and the urine organic acid profile was normal (Table 1).
Abdominal ultrasound revealed bilateral hypodysplastic kidneys (Figure 2). The liver and biliary systems appeared normal. Cardiac ultrasound, cranial magnetic resonance imaging (MRI), spinal MRI, and eye examination (including fundus and slit lamp examination) revealed no obvious abnormalities.
Target genes were captured with the Clinical 4000 Pathogenic Gene Package (Guangzhou Jia-Jian Medical Testing, Guangzhou, China), which includes 4,047 genes associated with known Mendelian genetic diseases and genes for typical renal abnormalities like HNF1B and other renal ciliopathies and is based on the OMIM database (https://omim.org/). We identified a heterozygous variation in intron 33 of the NOTCH2 gene (c.5930-2A > G) but no variants of the JAG1 gene or any other variants of interest. The family members of the patient were also tested for the target variation by Sanger sequencing. His parents did not carry this mutation, suggesting that this was a de novo mutation. His parents had none of the clinical abnormalities seen in the baby. Transcriptomic sequencing was used to verify the splice site change at the RNA level caused by the variant, thus confirming that the c.5930-2A > G variant could lead to the skipping of exon 33, thereby leading to alterations in NOTCH2 mRNA splicing (Figure 3).
Next, we performed whole exome sequencing (WES) to analyze the coding exons and the exon-intron boundaries of protein-coding genes (Cipher Gene, Beijing, China), which included a special focus on genes affecting renal abnormalities. However, in addition to the c.5930-2A > G mutation in NOTCH2, no other genetic mutations were detected that matched the patient's phenotype.
In conclusion, ALGS was diagnosed by considering the results of molecular diagnosis, clinical features, ultrasound, and other auxiliary examinations.