Severe neurodevelopmental disease caused by a homozygous TLK2 variant

Abstract

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

C1 [Topf, Ana; Balaraju, Sunitha; Thompson, Rachel; Horvath, Rita] Newcastle Univ, Inst Med Genet, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England.

[Oktay, Yavuz; Yilmaz, Elmasnur; Sonmezler, Ece; Hiz, Semra] Dokuz Eylul Univ, Izmir Biomed & Genome Ctr, Hlth Campus, Izmir, Turkey.

[Oktay, Yavuz] Dokuz Eylul Univ, Sch Med, Dept Med Biol, Izmir, Turkey.

[Oktay, Yavuz; Yilmaz, Elmasnur; Sonmezler, Ece] Dokuz Eylul Univ, Izmir Int Biomed & Genome Inst, Izmir, Turkey.

[Yis, Uluc; Hiz, Semra] Dokuz Eylul Univ, Sch Med, Dept Paediat Neurol, Izmir, Turkey.

[Laurie, Steven; Lochmueller, Hanns] Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona, Spain.

[Roos, Andreas] ISAS, Leibniz Inst Analyt Wissensch, Dortmund, Germany.

[Roos, Andreas] Univ Duisburg Essen, Univ Childrens Hosp, Fac Med, Pediat Neurol, Essen, Germany.

[MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.

[MacArthur, Daniel G.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA.

[Yaramis, Ahmet] Diyarbakir Mem Hosp, Pediat Neurol Clin, Diyarbakir, Turkey.

[Gungor, Serdal] Inonu Univ, Fac Med, Turgut Ozal Res Ctr, Dept Paediat Neurol, Malatya, Turkey.

[Lochmueller, Hanns] Univ Freiburg, Med Ctr, Fac Med, Dept Neuropediat & Muscle Disorders, Freiburg, Germany.

[Lochmueller, Hanns] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada.

[Lochmueller, Hanns] Ottawa Hosp, Dept Med, Div Neurol, Ottawa, ON, Canada.

[Horvath, Rita] Univ Cambridge, Sch Clin Med, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge, England.