PMC6664049_01
Clinical features of the index case. (A) Facial appearance of the patient, showing alopecia and sharp ears. (B) Brain MRI demonstrates periventricular white matter hyperintensities, ventriculomegaly, and a thin corpus callosum.
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F1
The patient developed alopecia universalis at age 8 and painful swollen ankles and recurrent pathological fractures at 25 (Figure 1A). The magnetic resonance imaging showed periventricular white matter hyperintensities, mild ventriculomegaly, and dilation of the subarachnoid spaces, small lacunar infarcts, a thin corpus callosum, and basal ganglia calcification (Figure 1B).
Pedigree and genetic findings of the index case. (A) Pedigree of the family and recorded clinical phenotypes. (B) IGV (Integrative Genomics View) visualization (right panel) of the chr6:41,127,528A>G (GRCh37/hg19) splice-site variant c.482+2T>C in patient (homozygous) and relatives (heterozygous). The variant, disrupting the donor splice site of TREM2 intron 3, is annotated in both ClinVar (#RCV000050138.1) and HGMD (#CS022111) as a disease-causing/likely pathogenic and has an extremely rare allele frequency in population databases (gnomAD: 0.0008126%; ExAC: 0.00165%), with only two reported heterozygous individuals in the European Non-Finnish population and no homozygotes. The variant is included in one of the numerous regions of homozygosity (chr6:24,747,411-42,365,687). Read depths (DP) and Mutant Allele Fraction (MAF) of the variant are shown for each member of the family. Sanger sequencing confirmation of the TREM2 variant is shown in the left panel.
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F2
TREM2 homozygous splice-donor variant (NM_018965.3:c.482+2T>C) in the proband, falling in one of the detected ROHs and affecting the splicing of exon 3, as previously demonstrated. This variant was at the heterozygous state in the healthy parents and sister (Figure 2B).
PMC6664049_02