Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

• Published in: Human genetics Vol. 136; no. 4; pp. 463 - 479
• Main Authors: Depienne, Christel, Nava, Caroline, Keren, Boris, Heide, Solveig, Rastetter, Agnès, Passemard, Sandrine, Chantot-Bastaraud, Sandra, Moutard, Marie-Laure, Agrawal, Pankaj B., VanNoy, Grace, Stoler, Joan M., Amor, David J., Billette de Villemeur, Thierry, Doummar, Diane, Alby, Caroline, Cormier-Daire, Valérie, Garel, Catherine, Marzin, Pauline, Scheidecker, Sophie, de Saint-Martin, Anne, Hirsch, Edouard, Korff, Christian, Bottani, Armand, Faivre, Laurence, Verloes, Alain, Orzechowski, Christine, Burglen, Lydie, Leheup, Bruno, Roume, Joelle, Andrieux, Joris, Sheth, Frenny, Datar, Chaitanya, Parker, Michael J., Pasquier, Laurent, Odent, Sylvie, Naudion, Sophie, Delrue, Marie-Ange, Le Caignec, Cédric, Vincent, Marie, Isidor, Bertrand, Renaldo, Florence, Stewart, Fiona, Toutain, Annick, Koehler, Udo, Häckl, Birgit, von Stülpnagel, Celina, Kluger, Gerhard, Møller, Rikke S., Pal, Deb, Jonson, Tord, Soller, Maria, Verbeek, Nienke E., van Haelst, Mieke M., de Kovel, Carolien, Koeleman, Bobby, Monroe, Glen, van Haaften, Gijs, Attié-Bitach, Tania, Boutaud, Lucile, Héron, Delphine, Mignot, Cyril
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2017; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Basic Medicine; Biomedical and Life Sciences; Biomedicine; Chromosome Deletion; Chromosomes, Human, Pair 1; Epilepsy; Gene Function; Gene mutation; Genes; Genetic aspects; Genetic research; Genetics; Genomics; Genotype & phenotype; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Hospitals; Human Genetics; Humans; Intellectual disabilities; Kinases; Life Sciences; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Metabolic Diseases; Microcephaly; Molecular Medicine; Mutation; Neurodevelopmental Disorders - genetics; Original Investigation; Phenotype; Phenotypes; Repressor Proteins - genetics; Surgery; Australia; France; Paris France; Seizure Onset; Corpus Callosum; Microcephaly; Intellectual Disability
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-017-1772-0

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes,
AKT3
,
HNRNPU
and
ZBTB18
are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with
ZBTB18
mutations and seven with
HNRNPU
mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in
HNRNPU
and
ZBTB18
to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that
AKT3
haploinsufficiency is the main driver for microcephaly, whereas
HNRNPU
alteration mostly drives epilepsy and determines the degree of intellectual disability.
ZBTB18
deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance.
ZBTB18
may also contribute to microcephaly and
HNRNPU
to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of
AKT3, ZBTB18
and
HNRNPU
in humans.