Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in <i>POR</i> gene: Antley‐bixler syndrome phenotype in three sibling fetuses

Tzetis, Maria; Konstantinidou, Anastasia; Sofocleous, Christalena; Kosma, Konstantina; Mitrakos, Anastasios; Tzannatos, C.; Kitsiou-Tzeli, Sofia

doi:10.1002/bdra.23492

Cited by 14 publications

(9 citation statements)

References 14 publications

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“…The mutation c.1370G > A (p.Arg457His) has been detected in patients diagnosed with Antley-Bixler syndrome [20, 21]. The other mutations have also been reported in recent years [22, 23]. The mutation c.744C > G (p.Tyr248*) is a nonsense mutation that prematurely terminates the encoding of the POR protein at amino acid 248 (the unmutated protein is 680 amino acids long).…”

Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

et al. 2019

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Background This study aims to provide genetic diagnoses for 30 cases of fetal skeletal dysplasia, and a molecular basis for the future prenatal diagnosis of fetal skeletal dysplasia. Methods A total of 30 cases of fetal skeletal dysplasia detected with ultrasound between January 2014 and June 2017 were analyzed. Among these fetuses, 15 fetuses had local skeletal malformations, while 15 fetuses had short limb malformations. Samples of fetal umbilical cord blood, amniotic fluid, and/or aborted tissue were collected from all cases. Karyotyping, whole genome sequencing, and targeted next-generation sequencing of skeletal disease-related pathogenic genes were performed, as needed. Blood samples were taken from the parents for verification using Sanger sequencing. Results Among the 30 cases of fetal skeletal dysplasia, two cases were diagnosed with trisomy 18. However, none of these cases were identified with any microdeletions or microreplications associated with skeletal dysplasia. Among the 28 chromosomally normal cases with fetal skeletal dysplasia, 21 cases were detected with mutations in genes related to skeletal diseases. Furthermore, collagen gene mutations were detected in six fetuses with short limb malformations, while heterozygous disease-causing mutations in the fibroblast growth factor receptor 3 ( FGFR3 ) gene were detected in seven fetuses. The remaining fetuses carried mutations in other various genes, including tumor protein p63 ( TP63 ), cholestenol delta-isomerase ( EBP ), cholinergic receptor nicotinic gamma subunit ( CHRNG ), filamin B ( FLNB ), and SRY-box 9 ( SOX9 ). Three compound heterozygous mutations in CHRNG , COL11A2 and SOX9 were carried by phenotypically healthy parents. Conclusion Targeted next-generation sequencing can significantly improve the prenatal diagnoses of fetal skeletal dysplasia, providing parents with more precision medicine, and improved genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

et al. 2019

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“…Notably, our patient in this study carried compound heterozygosity of a p.R457H missense variant and a novel exon 5 deletion in the POR gene, manifesting as severe ABS malformations, cardiac defects, and early demise in infancy. In another study, severe dysmorphic and skeletal malformations were found in three sibling fetuses with compound heterozygosity in the POR gene; one mutation was a copy number deletion, and the other was a p.A287P missense mutation (41).…”

Section: Discussionmentioning

confidence: 94%

Antley-Bixler syndrome arising from compound heterozygotes in the P450 oxidoreductase gene: a case report

Li¹,

Zhao

Xie³

et al. 2021

Transl Pediatr

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Antley-Bixler syndrome (ABS), first described by Antley and Bixler in 1975, is a rare skeletal malformation syndrome (1). The most characteristic clinical features of ABS patients include midface hypoplasia, craniosynostosis, radioulnar synostosis, choanal atresia or stenosis, femoral bowing and fractures, joint contractures, and arachnodactyly (2).Studies have shown that ventriculoperitoneal shunts are clinically required for treating craniosynostosis-induced hydrocephalus, and tracheotomy is usually provided to ABS patients with extreme midface hypoplasia and respiratory difficulties. In the neonatal period, the mortality rate of ABS is reportedly around 80% and is primarily caused by

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“…Furthermore, the analysis of the FAD binding domain reveals the presence of 10 POR mutations (Y326D, L374H, M408L, G413S, R457H, Y459H, R498P, A503V and G504R) ( Figure 5 ). In this group, R457H is the most prevalent mutation found in the Asian population, especially Japanese individuals, presenting with clinical phenotypes varying from mild to severe [ 3 , 13 , 15 , 16 , 18 , 19 , 20 , 21 , 24 , 25 , 27 , 29 , 41 , 42 , 43 , 47 , 48 , 49 , 53 ]. The R457 is located at the binding site of FAD where it closely interacts with the FAD cofactor ( Figure 7 C).…”

Section: Resultsmentioning

confidence: 99%

“…In this group the A287P mutation commonly found in the Caucasian population accounted for 40% residual activity of POR. The residue A287 plays an important role in stabilizing the beta-sheet structure ( Figure 7 D), and its substitution with Proline would have deleterious effects on the beta-sheet secondary structure, resulting in severe bone defects and sexual development disorders as seen in PORD patients [ 3 , 8 , 13 , 15 , 17 , 18 , 22 , 30 , 32 , 35 , 36 , 37 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase

et al. 2022

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Cytochrome P450 oxidoreductase (POR) is a membrane-bound flavoprotein that helps in transferring electrons from its NADPH domain to all cytochrome P450 (CYP450) enzymes. Mutations in the POR gene could severely affect the metabolism of steroid hormones and the development of skeletal muscles, a condition known as Cytochrome P450 oxidoreductase deficiency (PORD). PORD is associated with clinical presentations of disorders of sex development, Antley and Bixler’s syndrome (ABS), as well as an abnormal steroid hormone profile. We have performed an in silico analysis of POR 3D X-ray protein crystal structure to study the effects of reported mutations on the POR enzyme structure. A total of 32 missense mutations were identified, from 170 PORD patients, and mapped on the 3D crystal structure of the POR enzyme. In addition, five of the missense mutations (R457H, A287P, D210G, Y181D and Y607C) were further selected for an in-depth in silico analysis to correlate the observed changes in POR protein structure with the clinical phenotypes observed in PORD patients. Overall, missense mutations found in the binding sites of POR cofactors could lead to a severe form of PORD, emphasizing the importance of POR cofactor binding domains in transferring electrons to the CYP450 enzyme family.

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Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in POR gene: Antley‐bixler syndrome phenotype in three sibling fetuses

Cited by 14 publications

References 14 publications

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases

Antley-Bixler syndrome arising from compound heterozygotes in the P450 oxidoreductase gene: a case report

In Silico Analysis of PORD Mutations on the 3D Structure of P450 Oxidoreductase

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