Jos Jansen

3 73 TMEM199 Deficiency is characterized by elevated liverenzymes, hypercholesterolemia and abnormal glycosylation Table 1. Genotype and phenotype of TMEM199 deficient families Family F1 Family F2 Family F3 Individuals (y.o.b.) F1-II2 (’90) F1-II3 (’98) F2-II2 (’74) F3-II1 (’92) Genotype Genomic change (Chr17(GRCh37)) g.26684713C > A g.26684733G > C / g.26687551G > A g.26684785G > C cDNA change Homozygous c.20C > A Compound heterozy- gous c.40G > C / c.376-1G > A Homozygous c. 92G > C Protein change p.Ala7Glu p.Ala14Pro / p.0? p.Arg31Pro Allele frequency (ExaC browser) 0 0 / 0 5.002e-05 PhyloP 0.29 3.19 / NA 1.09 SIFT Not tolerated Tolerated / NA Tolerated PolyPhen 2.0 (score) Possibly damaging (score 0.609) Probably damaging (score 0.990) / NA Probably damaging (score 0.991) MutationTaster Polymorphism Disease causing / NA Disease causing Grantham distance 107 27/ NA 103 Phenotype Elevated aminotrans- ferases + + + Elevated alkaline phos- phatase ++ ++ ++ Steatosis + + n.d. Elevated cholesterol & LDL-C + + + Low ceruloplasmin + + + Glycosylation profile Abnormal N- and O-glycosylation Abnormal N-glycosyla- tion Abnormal N- and O-glycosylation Abbreviations are as follows: y.o.b., year of birth; LDL-C, low-density lipoprotein cholesterol; NA, not applicable; n,d, not determined