@article {726, title = {PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.}, journal = {Eur J Med Genet}, volume = {63}, year = {2020}, month = {2020 Feb}, pages = {103660}, abstract = {

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

}, keywords = {Brain Edema, Databases, Genetic, Edema, Epileptic Syndromes, Female, Finland, Heterozygote, Humans, Infant, Newborn, Mutation, Missense, Neurodegenerative Diseases, Nuclear Proteins, Optic Atrophy, Phenotype, Spasms, Infantile, Transcription Factors, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2019.04.017}, author = {{\~O}unap, Katrin and Muru, Kai and {\~O}iglane-Shlik, Eve and Ilves, Pilvi and Pajusalu, Sander and Kuus, Imbi and Wojcik, Monica H and Reimand, Tiia} } @article {755, title = {Severe neurodevelopmental disease caused by a homozygous TLK2 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {383-387}, 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.

}, keywords = {Adult, Cerebellum, Child, Developmental Disabilities, Female, Heterozygote, Homozygote, Humans, Infant, Male, Mutation, Missense, Nervous System Malformations, Pedigree, Protein Kinases, Spasms, Infantile}, issn = {1476-5438}, doi = {10.1038/s41431-019-0519-x}, author = {Topf, Ana and Oktay, Yavuz and Balaraju, Sunitha and Yilmaz, Elmasnur and Sonmezler, Ece and Yis, Uluc and Laurie, Steven and Thompson, Rachel and Roos, Andreas and MacArthur, Daniel G and Yaramis, Ahmet and G{\"u}ng{\"o}r, Serdal and Lochm{\"u}ller, Hanns and Hiz, Semra and Horvath, Rita} } @article {334, title = {A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {343-351}, abstract = {

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who~underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p~= 1.25~{\texttimes} 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

}, keywords = {Alleles, Amino Acid Sequence, Brain, Cataract, Child, Child, Preschool, Female, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Missense, Neoplasm Proteins, Pedigree, Phenotype, Repressor Proteins, Spasms, Infantile}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.12.013}, author = {Schoch, Kelly and Meng, Linyan and Szelinger, Szabolcs and Bearden, David R and Stray-Pedersen, Asbjorg and Busk, Oyvind L and Stong, Nicholas and Liston, Eriskay and Cohn, Ronald D and Scaglia, Fernando and Rosenfeld, Jill A and Tarpinian, Jennifer and Skraban, Cara M and Deardorff, Matthew A and Friedman, Jeremy N and Akdemir, Zeynep Coban and Walley, Nicole and Mikati, Mohamad A and Kranz, Peter G and Jasien, Joan and McConkie-Rosell, Allyn and McDonald, Marie and Wechsler, Stephanie Burns and Freemark, Michael and Kansagra, Sujay and Freedman, Sharon and Bali, Deeksha and Millan, Francisca and Bale, Sherri and Nelson, Stanley F and Lee, Hane and Dorrani, Naghmeh and Goldstein, David B and Xiao, Rui and Yang, Yaping and Posey, Jennifer E and Martinez-Agosto, Julian A and Lupski, James R and Wangler, Michael F and Shashi, Vandana} } @article {44, title = {PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies.}, journal = {Pediatr Neurol}, volume = {60}, year = {2016}, month = {2016 Jul}, pages = {83-7}, abstract = {

BACKGROUND: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

METHODS: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

RESULTS: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

CONCLUSIONS: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

}, keywords = {Brain Edema, Child, Child, Preschool, Female, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Infant, Male, Mutation, Neurodegenerative Diseases, Optic Atrophy, Phenotype, Protein Serine-Threonine Kinases, Spasms, Infantile}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2016.03.011}, author = {Gawlinski, Pawel and Posmyk, Renata and Gambin, Tomasz and Sielicka, Danuta and Chorazy, Monika and Nowakowska, Beata and Jhangiani, Shalini N and Muzny, Donna M and Bekiesinska-Figatowska, Monika and Bal, Jerzy and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Wiszniewski, Wojciech} }