The clinical phenotype with gastrostomy and abdominal wall infection in a pediatric patient with Takenouchi-Kosaki syndrome due to a heterozygous c.191A &gt; G (p.Tyr64Cys) variant in CDC42: a case report

Szczawińska-Popłonyk, Aleksandra; Popłonyk, Natalia; Badura-Stronka, Magdalena; Juengling, Jerome; Huhn, Kerstin; Biskup, Saskia; Bancerz, Bartłomiej; Walkowiak, Jarosław

doi:10.3389/fgene.2023.1108852

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…These findings emphasize that even with the presence of the same variants within the same ethnicity, discordant phenotypes can emerge, which may be explained by indicating the potential influence of other modifier genes in shaping the observed outcomes. Intriguingly, the partial phenotype observed in our patients-including intellectual disability, hearing loss, facial dysmorphism, and camptodactyly-significantly overlaps with those seen in a patient with Takenouchi-Kosaki syndrome and a heterozygous c.191A>G (p.Tyr64Cys) variant in CDC42 [32].…”

Section: Discussionsupporting

confidence: 56%

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Susgun,

Ben-Mahmoud,

Rüschendorf

et al. 2024

Human Mutation

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Glycosylphosphatidylinositols (GPIs) anchor over 150 proteins as GPI-anchored proteins (GPI-APs) with crucial roles in diverse biological processes. The highly conserved biosynthesis of GPI-APs involves precise steps with at least 21 genes, categorized as PIG and PGAP genes. Pathogenic variants in these genes are linked to human diseases, highlighting the importance of each biosynthesis step. PGAP2 stands out among these genes due to its association with an expanded clinical spectrum of neurodevelopmental disorder (NDD) phenotypes with biallelic pathogenic variants. We present four patients from two families, one consanguineous and the other nonconsanguineous, each displaying distinct clinical presentations, including intellectual disability, hyperphosphatasia, hearing impairment, and epilepsy, as well as craniofacial and digital anomalies. Genetic analyses revealed homozygous and novel compound heterozygous missense variants in PGAP2 in four affected individuals, confirming the molecular diagnosis of hyperphosphatasia with impaired intellectual development syndrome 3 (HPMRS3). Importantly, the three amino acids affected by missense variants exhibit complete conservation in 10 vertebrate species, illuminating their crucial role in the gene’s functionality. Protein modeling provided additional evidence for the pathogenicity of the three substitutions, demonstrating their detrimental impact on protein folding and putative protein-protein interactions, ultimately leading to impaired protein function. The four patients in our study displayed common phenotypic features, such as brachydactyly, camptodactyly, and syndactyly, which have not been previously documented in individuals with PGAP2 variants. Notably, the occurrence of macrocephaly in two affected brothers from a consanguineous Pakistani family represents a novel finding. These previously unreported digital anomalies, along with macrocephaly and the identification of novel compound heterozygous variants, contribute to the expansion of the phenotypic and genotypic spectrum of HPMRS3 associated with PGAP2 variants.

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Section: Discussionsupporting

confidence: 56%

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Susgun,

Ben-Mahmoud,

Rüschendorf

et al. 2024

Human Mutation

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“…Pathogenic variants in RAC1 cause the autosomal dominant inherited intellectual developmental disorder type 48 (OMIM # ), while heterozygous pathogenic variants in CDC42 can cause Takenouchi-Kosaki syndrome (OMIM # ). Patients with atrial and/or ventricular septal defects have been described in both syndromes ( Martinelli et al, 2018 ; Reijnders et al, 2017 ; Szczawińska-Popłonyk et al, 2023 ). Furthermore, Rac1 deficiency in murine neonatal cardiomyocytes leads to defects in lamellipodia formation, cell elongation and polarity, as well as in increased apoptosis and reduced expression of the cardiac transcription factors Gata4, Tbx5, Nkx2.5 and Hand2 ( Leung et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Fbrsl1 is required for heart development in Xenopus laevis and de novo variants in FBRSL1 can cause human heart defects

Berger,

Gerstner,

Horstmann

et al. 2024

Disease Models &Amp; Mechanisms

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De novo truncating variants in Fibrosin-like protein 1 (FBRSL1), a member of the AUTS2 gene family, cause a disability syndrome, including organ malformations such as heart defects. Here, we use Xenopus laevis to investigate whether Fbrsl1 plays a role in heart development. Xenopus laevis fbrsl1 is expressed in tissues relevant for heart development and morpholino-mediated knockdown of Fbrsl1 results in severely hypoplastic hearts. Our data suggest that Fbrsl1 is required for the development of the first heart field, which contributes to the ventricle and the atria, but not for the second heart field, which gives rise to the outflow tract. The morphant heart phenotype could be rescued using a human N-terminal FBRSL1 isoform that contains an alternative exon, but lacks the AUTS2 domain. N-terminal isoforms carrying patient variants failed to rescue. Interestingly, a long human FBRSL1 isoform, harboring the AUTS2 domain, did also not rescue the morphant heart defects. Thus, our data suggest that different FBRSL1 isoforms may have distinct functions and that only the short N-terminal isoform, appears to be critical for heart development.

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Auditory and Language Abilities in Children with Takenouchi–Kosaki Syndrome: A Systematic Review

Caragli,

Genovese,

Parretta

et al. 2024

Genes

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Takenouchi–Kosaki syndrome (TKS) is a rare congenital disease caused by a de novo mutation in the Cell Division Cycle 42 (CDC42) gene. Patients with TKS present facial and body dysmorphisms, hematologic and immune dysregulation, intellectual disability, neurodevelopmental delay and hearing loss. The aim of this study is to review the literature, focusing on hearing and language abilities in children with TKS. A systematic search on PubMed, Scopus and Web of Science databases was performed, including twelve studies for a total of 13 patients. Hearing loss (HL) occurs in a great percentage of patients (84.6%); nonetheless, auditory threshold, severity of HL and language abilities were reported in a few cases. In two studies, auditory rehabilitation strategies were described. Although several studies have investigated the hematological features of TKS, still only a few authors have focused on the audiological and language abilities of these children. Given the fact that HL has a significant impact on behaviors, communications skills, and quality of life, it is important to adequately assess and rehabilitate patients early with this syndrome. Further studies are needed to improve the knowledge about this topic and improve the quality of life of patients with TKS.

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The clinical phenotype with gastrostomy and abdominal wall infection in a pediatric patient with Takenouchi-Kosaki syndrome due to a heterozygous c.191A > G (p.Tyr64Cys) variant in CDC42: a case report

Cited by 3 publications

References 39 publications

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)

Fbrsl1 is required for heart development in Xenopus laevis and de novo variants in FBRSL1 can cause human heart defects

Auditory and Language Abilities in Children with Takenouchi–Kosaki Syndrome: A Systematic Review

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