WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins

Сорокина, Е. А.; Reis, Linda M.; Thompson, Samuel; Agre, Katherine; Babovic‐Vuksanovic, Dusica; Ellingson, Marissa S.; Hasadsri, Linda; Bever, Yolande van; Semina, Elena V.

doi:10.1007/s00439-021-02384-y

Cited by 9 publications

(15 citation statements)

References 38 publications

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“…Ophthalmological anomalies common among these 3 entities (Table 1) support that this axis is also importantly involved in eye development [Sakaguchi et al, 2021]. Immunofluorescence staining experiments localizing WDR37, PACS1, and PACS2 proteins in the cytoplasm around the nucleus of human lens epithelial cells [Sorokina et al, 2021], and demonstrating their expression in the eye and retina [Stelzer et al, 2016], provide additional arguments for this probable pathogenic relationship, although its pathophysiology remains unknown.…”

Section: Discussionmentioning

confidence: 93%

“…PACS1-related NDD, WDR37-related NOCGUS, and the PACS2-related syndrome can also commonly present with intellectual disability, epilepsy, structural brain and heart anomalies, feeding problems, and genitourinary defects, typically more severe among affected individuals with WDR37-related NOCGUS [Sakaguchi et al, 2021;Sorokina et al, 2021]. This shared phenotype has been previously related to the fact that WDR37-PACS1-PACS2 are interacting proteins [Sakaguchi et al, 2021].…”

Section: Discussionmentioning

confidence: 94%

“…The PACS1 gene and its paralog, PACS2 (MIM 610423), are the major binding partners of the WD repeat domain 37 gene (WDR37; MIM 618586), which has an important role in gene expression, signal transduction, protein metabolism, cell cycle, and immune system pathways, among other functions [Sorokina et al, 2021]. Pathogenic variants in the WDR37 and PACS2 genes cause WDR37-related neurooculocardiogenitourinary syndrome (WDR37-related NOCGUS; MIM 618652) and PACS2-related syndrome (developmental and epileptic encephalopathy 66; MIM 618067), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Pathogenic variants in the WDR37 and PACS2 genes cause WDR37-related neurooculocardiogenitourinary syndrome (WDR37-related NOCGUS; MIM 618652) and PACS2-related syndrome (developmental and epileptic encephalopathy 66; MIM 618067), respectively. It has been noted that both syndromes have a very similar facial gestalt with the PACS1-related NDD [Sakaguchi et al, 2021], along with other generalized affectations in common [Kanca et al, 2019;Reis et al, 2019;Sakaguchi et al, 2021;Sorokina et al, 2021]. Therefore, these 3 syndromes have been included within a new group of diseases called disorders of the WDR37-PACS1-PACS2 axis [Sakaguchi et al, 2021;Rylaarsdam et al, 2022].…”

Section: Introductionmentioning

confidence: 99%

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First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations

et al. 2022

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Introduction: PACS1-related neurodevelopmental disorder (PACS1-related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement. Case Presentation: Here, we describe 4 individuals with PACS1-related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1-related NDD. Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1-related NDD and the overlaps with WDR37- and PACS2-related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1-related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37-PACS1-PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations

et al. 2022

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“…1 In humans, missense variants in WDR37 cause neurooculocardiogenitourinary syndrome (NOCGUS; OMIM ID: 618652), an autosomal dominant multisystemic disorder characterized by variable features such as speci c facies; ocular coloboma; signi cant neurological de cits with brain malformations; anomalies of cardiovascular, genitourinary, skeletal, and gastrointestinal systems; and postnatal growth failure. 1,2,4,5 To date, no frameshift, or nonsense variants in WDR37 have been reported in humans. We report the case of a patient with NOCGUS who had a splicing variant of WDR37 and whose features were less severe than those of previously reported cases of missense variants in WDR37.…”

Section: Introductionmentioning

confidence: 99%

Splicing Variant of WDR37 in a Case of Neurooculocardiogenitourinary Syndrome

Samejima

Nakashima

Shibasaki

et al. 2023

Preprint

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Background Neurooculocardiogenitourinary syndrome (NOCGUS), a multisystemic syndrome characterized by motor disorder, intellectual disability, seizures, abnormal brain structure, ocular diseases, and cardiac diseases, has been reported with missense variant of WD repeat-containing protein 37 (WDR37) in humans. This report aimed to identify the cause of neurooculocardiogenitourinary syndrome (NOCGUS) in an affected patient. Case presentation We identified a de novo intronic 4-bp deletion of WDR37, c.727 − 27_727-24del, which were predicted to cause abnormal splicing by SpliceAI, in the patient with NOCGUS. Reverse transcription polymerase chain reaction (RT-PCR) revealed intron retention of 63 base pairs before exon 10 in messenger RNA, which was predicted to insert 21 additional aberrant amino acids (p.S242_I243insLCQKKLKISRKCLFWPSLWQQ). The patient had novel phenotypes, anal atresia, and polycystic kidney, in addition to intellectual disability, seizures, cerebellar vermian anomaly, and coloboma, which are typical in NOCGUS. We did not observe motor impairments or cardiovascular anomalies. Conclusion This is the first reported case of NOCGUS with the splicing variant of WDR37, which manifests with distinctive but variable features. Our findings may expand a possible phenotypic expression of NOCGUS.

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