Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy

Wong, Hui Hui; Seet, Sze Hwee; Maier, Michael; Gürel, Ayşe; Traspas, Ricardo Moreno; Lee, Cheryl; Zhang, Shan; Talim, Beril; Loh, Abigail; Chia, Crystal Y.; Teoh, Tze Shin; Sng, Danielle; Rensvold, Jarred W.; Ünal, Şule; Çepni, Ece; Nathan, Fatima Megala; Sirota, Fernanda L.; Liang, Chao; Yaralı, Neşe; Şimşek‐Kiper, Pelin Özlem; Mitani, Tadahiro; Ceylaner, Serdar; Arman-Bilir, Ozlem; Mbarek, Hamdi; Gümrük, Fatma; Efthymiou, Stéphanie; Çi̇men, Deniz Uğurlu; Georgiadou, Danai; Sotiropoulou, Kortessa; Houlden, Henry; Paul, Franziska; Pehlivan, Davut; Lainé, Candice; Chai, Guoliang; Ali, Nur Ain; Choo, Siew Chin; Keng, Soh Sok; Boisson, Bertrand; Yilmaz, Elanur; Xue, Shifeng; Coon, Joshua J.; Ly, Thanh Thao Nguyen; Gilani, Naser; Hasbini, Dana; Kayserili, Hülya; Zaki, Maha S.; Isfort, Robert J.; Ordonez, Natalia; Tripolszki, Kornélia; Bauer, Péter; Rezaei, Nima; Seyedpour, Simin; Khotaei, Ghamar Taj; Bascom, Charles C.; Maroofian, Reza; Chaâbouni, M; Alsubhi, Afaf; Eyaid, Wafaa; Işıkay, Sedat; Gleeson, Joseph G.; Lupski, James R.; Casanova, Jean Laurent; Pagliarini, David J.; Akarsu, Nurten; Maurer‐Stroh, Sebastian; Çetinkaya, Arda; Bertoli‐Avella, Aida M.; Mathuru, Ajay S.; Ho, Lena; Bard, Frédéric; Reversade, Bruno

doi:10.1016/j.ajhg.2021.06.009

Cited by 1 publication

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…with recently published C2orf69 variants, wherein the majority are frameshift variants and all map to the UPF0565 uncharacterized domain of C2orf69 (Figure 2b; Lausberg et al, 2021;Wong et al, 2021). Together with this report, a total of six frameshift, one in-frame deletion, and one C-terminal nonsense variant in C2orf69 have been discovered in individuals with COXPD53 (Table S1).…”

Section: Features Of the Discovered Novel Frameshift Variant In P1 Alignsupporting

confidence: 82%

“…The c.187_191dupGCCGA, p.D64Efs*56 frameshift variant is likely pathogenic, according to the American College of Medical Genetics (ACMG) standards and guidelines (Richards et al, 2015). Evidence in support of this pathogenicity classification include previously identified pathogenic loss-of-function variants inC2orf69, one of which localizes to the same exon as c.187_191dupGCCGA (Lausberg et al, 2021;Wong et al, 2021).…”

Section: Case Reportmentioning

confidence: 99%

“…Newly characterized types of COXPD is COXPD type 53 (COXPD53 [MIM: 619423]), an autosomal recessive NDD caused by variants in the gene C2orf69 (Lausberg et al, 2021; Wong et al, 2021). Two recent reports have identified seven predicted loss‐of‐function variants in the genetic etiology of COXPD53, which is defined by early childhood onset of symptoms such as seizures, global developmental delay, microcephaly, structural brain defects, musculoskeletal anomalies, and autoinflammation.…”

Section: Introductionmentioning

confidence: 99%

“…Two recent reports have identified seven predicted loss‐of‐function variants in the genetic etiology of COXPD53, which is defined by early childhood onset of symptoms such as seizures, global developmental delay, microcephaly, structural brain defects, musculoskeletal anomalies, and autoinflammation. Findings from human cultured neurons provide evidence that C2orf69 functions in oxidative respiration and regulates mitochondrial membrane potential as well as the amount of glycogen branching enzyme 1 (Wong et al, 2021). Knockout of C2orf69 in zebrafish causes brain inflammation, epilepsy, and embryonic lethality—phenotypes consistent with human genetics findings (Wong et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Findings from human cultured neurons provide evidence that C2orf69 functions in oxidative respiration and regulates mitochondrial membrane potential as well as the amount of glycogen branching enzyme 1 (Wong et al, 2021). Knockout of C2orf69 in zebrafish causes brain inflammation, epilepsy, and embryonic lethality—phenotypes consistent with human genetics findings (Wong et al, 2021). However, our understanding of the precise molecular functions of C2orf69 are far from complete.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A novel biallelic frameshift variant in C2orf69 causing developmental regression, seizures, microcephaly, autistic features, and hypertonia

Werren,

Srinivasan,

Gowda

et al. 2023

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Combined oxidative phosphorylation deficiency type 53 (COXPD53) is an autosomal recessive neurodevelopmental disorder (NDD) caused by homozygous variants in the gene C2orf69. Here, we report a novel frameshift variant c.187_191dupGCCGA, p.D64Efs*56 identified in an individual with clinical presentation of COXPD53 with developmental regression and autistic features. The variant c.187_191dupGCCGA, p.D64Efs*56 represents the most N‐terminal part of C2orf69. Notable clinical features of COXPD53of the proband include developmental delay, developmental regression, seizures, microcephaly, and hypertonia. Structural brain defects of cerebral atrophy, cerebellar atrophy, hypomyelination, and thin corpus callosum were also observed. While we observe strong phenotypic overlap among affected individuals with C2orf69 variants, developmental regression and autistic features have not been previously described in individuals with COXPD53. Together, this case expands the genetic and clinical phenotypic spectrum of C2orf69‐associated COXPD53.

show abstract

Section: Features Of the Discovered Novel Frameshift Variant In P1 Alignsupporting

confidence: 82%