Phenotypic Prenatal Diagnosis of Chronic Granulomatous Disease: A Useful Tool in The Absence Of Molecular Diagnosis

Abstract

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disorder affecting the microbicidal function of the phagocytes. It is characterized by susceptibility to recurrent infections leading to significant morbidity and mortality. Antibacterial and antifungal prophylaxis, though, has significantly reduced the rate and severity of the infections; the breakthrough infections still remain a challenge. Currently, allogenic haematopoietic stem cell transplantation is the only curative option which is very expensive and unavailable for many due to lack of suitable donor. Thus, prenatal diagnosis (PND) forms an important component of management in the affected families. PND is challenging in families approaching late in pregnancy with an uncharacterized molecular defect. In such cases, PND can be performed by analysis of NADPH activity of fetal blood (FB) neutrophils at 18-20 weeks of gestation. Cord blood samples at 18 weeks of gestation from healthy control were used to establish normal ranges for NBT and DHR. PND was offered for six pregnancies (NBT: n = 3, DHR: n = 6) with index cases of CGD confirmed by abnormal NBT and DHR analysis. NBT and DHR tests were found to be negative for all the six cases, confirming the same on samples post-delivery. NBT and DHR tests offer a rapid and sensitive PND of CGD in the absence of facilities for molecular diagnosis. It was observed that addition of CD15 along with CD45 led to an accurate DHR analysis. It is recommended to perform the diagnosis with adequate precautions only at centres with considerable experience and expertise in the diagnosis of CGD.

Clinical and genetic characteristics of Chinese pediatric patients with chronic granulomatous disease

“…To date, we detected CYBB variants in CGD patients, mostly involving exons 7 and 9, similar to that of previous studies . Mutation analysis remains an important tool for genetic counseling and prenatal diagnosis . Except for the CYBB variant, a previous study has shown that there are at least three types of AR‐CGD, which include NCF1 (20%), NCF2 (5%), and CYBA (5%) .…”

“…8,23 Mutation analysis remains an important tool for genetic counseling and prenatal diagnosis. 24 Except for the CYBB variant, a previous study has shown that there are at least three types of AR-CGD, which include NCF1 (20%), NCF2 (5%), and CYBA (5%). 8 However, in our study, we found AR-CGD is rare in Chinese pediatric patients, and CYBA is more common than the other two types.…”

Successful application of next‑generation sequencing for pre‑natal diagnosis in a pedigree with chronic granulomatosis disease

“…This variant was identified as the molecular cause of the disease and abnormal neutrophil respiratory burst function was also observed. In recent years, flow cytometry has been used for the pre-natal diagnosis of CGD (23). Flow cytometry is a fast and sensitive method for detecting CGD; however, the accuracy of this method requires further evaluation (24).…”

Application of Flow Cytometry in Primary Immunodeficiencies: Experience From India

“…Among them, a genotype could not be identified using flow cytometric evaluation in two patients. In a country like India with limited resources, the predominance of AR-CGD type, and a high frequency of consanguineous marriages, the flow cytometric classification of CGD patients remains a vital tool in the early diagnosis and guide for molecular characterization (by suggesting appropriate method) (44, 68) (Figure 9).…”

“…Molecular diagnosis may not be possible or available in all affected cases; thus, phenotypic prenatal diagnosis by cordocentesis for families with an index case having an immunophenotypically well-characterized PID is an apt alternative. Thus, phenotypic prenatal diagnosis by flow cytometry offers a simple and rapid tool compared to molecular characterization (68, 69).…”