The girl was the firstborn child of healthy nonconsanguineous Chinese parents from Anhui Province. She was cesarean born with a length of 47 cm (-2 SD), weight of 3180 g (-1 SD), and a head circumference of 31 cm (<-2 SD). From birth onward, she had feeding problems and febrile seizures, regularly. The electroencephalogram (EEG) was normal or slightly abnormal during the first year of life. She was able to sit unsupported around the age of 10 months and walk independently around the age of 23 months, and non-fluent motoric movements and hypoactivity were noted. She was described as having a broad-based clumsy tread, and exhibited a mild tremor. She started to pronounce syllables around 2 years old and used simple words around the age of 3 years. Nowadays, she could not speak with full sentences and presented with significantly lower IQ (67).
At 4 years old, the girl had a slender posture with a length of 90 cm (-1.5 SD) and presented with significantly smaller head size of 38.5 cm (<-2 SD) compared to the same age children. Typical facial dysmorphisms included deep-set eyes, pointed nasal tip, large ears, a downturned mouth, and micrognathia (Figure 1A). A cerebral magnetic resonance imaging (MRI) showed mild widened lateral ventricles, enlarged pericerebral spaces, high palate, a thin corpus callosum, and delayed myelination but without structural congenital anomalies (Figure 1B).
Chromosomal abnormalities and submicroscopic chromosomal imbalances at the whole genome level of the girl by CMA did not reveal any anomaly (data not shown). Using WES, a heterozygous nonsense variant (chr21:38865324C > A; c.930C > A; p.Tyr310*) in the coding region of exon 7 of the DYRK1A gene (NM_130436.2) was identified in the proband. Nevertheless, none of the mutation at this site was found in her parents (Figures 2A, B). Sanger sequencing confirmed this conclusion (Figure 2C).
The nonsense variant in the amino acid residue tyrosine 310, a perfectly conserved amino acid in DYRK1A and DYRK1A vertebrate orthologues, was a heterozygous truncation mutation and interfered with the protein kinase activity. This variant was absent from the Genome Aggregation Database browsers (gnomAD, ) and the Exome Aggregation Consortium databases (ExAC, ) or dbSNP (), which excluded that it represents a polymorphism. Meanwhile, the loss-of-function intolerance (pLI) for DYRK1A is 1.00, which is based on the ExAC sequencing data, suggesting strong intolerance to functional mutations. Taken together, we hypothesize that the nonsense mutation causes the severe clinical phenotype by ACMG recommendations for standards and guidelines for the interpretation of sequence variants. A heterozygous variant in PKHD1L1 (NM_177531.6: c.9352G>T, Glu3118*); a heterozygous variant in PRODH2 (NM_021232.1: c.457C>T, Arg153*) and a heterozygous variant in SDK2 (NM_001144952.2: c.1865delT, Leu622Argfs*29) was also identified, which were ruled out because the genes were recessive inheritance and only one variant of each gene was identified in the patient. Moreover, the phenotype of the patient was not consistent with the genes ( Supplementary Table S1 ).