PMC8430206_01
Timeline of symptoms and signs.
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F1
Global development was reportedly normal until 6 months of age, when hypotonia and failure to achieve motor milestones were first noticed and the patient was referred to our Child Neurology outpatient clinic (Figure 1).
MRI findings at age 11 years. (A) Coronal T2-weighted images showing PMG without an anterior-posterior gradient of involvement, including frontal cortex (closed arrow), parietal cortex (arrowhead) and occipital cortex (open arrow). There is relative sparing of the temporal lobes (asterisk). (B) Axial T2 image displaying diffuse white matter hypomyelination. (C) Sagittal T1 image highlighting pontine and cerebellar hypoplasia.
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F2
Repeat MRI at 11 years of age (Figure 2) was globally consistent with the above-mentioned features.
(A) Sanger sequencing chromatograms of the patient and parents. The patient is a homozygous carrier of the nonsense variant c.1504C>T. The variant was present in the heterozygous state in both parents. (B,C) Schematic of the ADGRG1 protein, showcasing the novel variant in the 7TM domain of the protein (p.Arg502*). 7TM, 7 transmembrane domain; GAIN, GPCR-Autoproteolysis-INducing domain; GPS, GPCR proteolysis site motif; PLL, Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-Like domain.
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F3
Segregation analysis through Sanger sequencing confirmed the presence of the variant in the homozygous state in the patient and revealed that both parents were heterozygous carriers (Figure 3A). The variant is located in the seven-transmembrane (7TM) domain of the ADGRG1 protein, which binds to a heterotrimeric G-protein complex and initiates downstream signaling (Figures 3B,C).