A Founder Effect of c.257+2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

Khaoula Ben-Farhat; Imen Ben-Mustapha; Meriem Ben-Ali; Karen Rouault; Saber Hamami; Najla Mekki; Amel Ben-Chehida; Beya Larguèche; Zohra Fitouri; Selim Abdelmoula; Monia Khemiri; Sihem Barsaoui; Mohamed-Neji Guediche; Samir Boukthir; Jalel Chemli; Mohamed-Ridha Barbouche

doi:10.1007/s10875-016-0299-9

Journal articles

A Founder Effect of c.257+2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

Khaoula Ben-Farhat ^{1, 2} Imen Ben-Mustapha ^{1, 2, 3, *} Meriem Ben-Ali ^{1, 2} Karen Rouault ⁴ Saber Hamami ⁵ Najla Mekki ^{1, 2, 3} Amel Ben-Chehida ⁶ Beya Larguèche ² Zohra Fitouri ⁷ Selim Abdelmoula ⁵ Monia Khemiri ⁷ Sihem Barsaoui ⁷ Mohamed-Neji Guediche ⁵ Samir Boukthir ⁷ Jalel Chemli ⁸ Mohamed-Ridha Barbouche ^{1, 2, 3}

* Corresponding author

1 UTM - Université de Tunis El Manar

2 LR11IPT02 - Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection

3 Faculté de Médecine de Tunis

4 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)

5 Département pédiatrique [Hôpital Fattouma Bourguiba - Monastir]

6 Department of Pediatrics [Tunis]

7 Béchir Hamza Children's Hospital

8 CHU Sahloul - Hôpital Universitaire Sahloul

Abstract : Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.

Keywords : consanguinity founder effect Tunisia Chronic granulomatous disease NCF2 gene

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Journal articles

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Life Sciences [q-bio]

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Submitted on : Thursday, December 29, 2016 - 10:04:23 AM
Last modification on : Wednesday, November 3, 2021 - 6:10:12 AM

A Founder Effect of c.257+2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

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A Founder Effect of c.257+2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients

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