title: Loss of function of PCDH12 underlies recessive microcephaly mimicking intrauterine infection.
abstract: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability.
  
  
  
  Identification of the responsible gene by whole exome sequencing and homozygosity mapping.
  
  
  
  Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12 p.R839X is <0.00001 worldwide. Genotyping PCDH12 p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12 p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability.
  
  
  
  Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Adi
authors.initials: A
authors.lastname: Aran
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Nuphar
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Ranit
authors.initials: R
authors.lastname: Jaron
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Shachar
authors.initials: S
authors.lastname: Zuckerman
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Hila
authors.initials: H
authors.lastname: Fridman
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Kohn
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Lara
authors.initials: L
authors.lastname: Kamal
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Segev
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Eyal
authors.initials: E
authors.lastname: Mazaki
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Ron
authors.initials: R
authors.lastname: Rabinowitz
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Ori
authors.initials: O
authors.lastname: Shen
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Ming
authors.initials: M
authors.lastname: Lee
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Mary Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle.
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle. lahad@szmc.org.il.
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging* / Q000254:growth & development; D015820:Cadherins / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000000981:diagnostic imaging / Q000235:genetics; D003937:Diagnosis, Differential; D005260:Female; D005317:Fetal Growth Retardation / Q000000981:diagnostic imaging / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008831:Microcephaly / Q000000981:diagnostic imaging* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000000981:diagnostic imaging; D011296:Prenatal Diagnosis; D000091363:Protocadherins; D013577:Syndrome; D014591:Uterine Diseases / Q000000981:diagnostic imaging
chemical_list: D015820:Cadherins; C113432:PCDH12 protein, human; D000091363:Protocadherins