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A Clinical Conundrum with Diagnostic and Therapeutic Challenge: a Tale of Two Disorders in One Case

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Abstract

Living organisms are exposed to exogenous and endogenous agents that affect genomic integrity by creating DNA double strand breaks (DSBs). These breaks are repaired by DNA repair proteins to maintain homeostasis. Defects in DNA repair pathways also affect lymphocyte development and maturation, as DSB sites are critical intermediates for rearrangements required for V(D)J recombination. Recent classifications for inborn errors of immunity (IEIs) have listed DNA repair defect genes in a separate group, which suggests the importance of these genes for adaptive and innate immunity. We report an interesting case of a young female (index P1) with mutations in two different genes, DCLRE1C and FANCA, involved in DNA repair pathways. She presented with clinical manifestations attributed to both defects. With the advent of NGS, more than one defect is increasingly identified in patients with IEIs. Familial segregation studies and appropriate functional assays help ascertain the pathogenicity of these mutations and provide appropriate management and genetic counseling.

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Data Availability

All data is available as electronic supplementary material.

Code Availability

Not applicable.

Abbreviations

ATM:

Ataxia telangiectasia mutated

BLM:

BLM RecQ Like Helicase

CBC:

Complete blood count

DCLRE1C:

DNA Cross-Link Repair 1C

DNMT3B:

DNA Methyltransferase 3 Beta

DSBs:

DNA double strand breaks

GINS1:

GINS Complex Subunit 1

IEIs:

Inborn errors of Immunity

LIG1:

DNA Ligase 1

LIG4:

DNA Ligase 4

MCM10:

Mini chromosome maintenance 10 replication initiation factor

MLPA:

Multiplex Ligation-dependent Probe Amplification

MRE11:

Meiotic recombination 11

NBS1:

Nijmegen breakage syndrome 1

NGS:

Next-generation sequencing

NHEJ1:

Non-homologous end-joining factor 1

PBS:

Phosphate buffer saline

PMS2:

PMS1 Homolog 2, Mismatch Repair System Component

pSMC1:

Phospho-structural maintenance of chromosomes

Rad50:

RAD50 Double Strand Break Repair Protein

RNF168:

E3 ubiquitin-protein ligase RNF168

TCR:

T-cell receptors

V(D)J recombination:

Variability, diversity, and joining recombination

γH2AX:

Gamma H2A histone family member X

FISH:

Fluorescence in situ hybridization

FFP:

Fresh frozen plasma

PRC:

Packed red cell

DLBCL:

Diffuse large B cell lymphoma

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Acknowledgements

We like to thank patient and her family members for their cooperation during this study. Technical support received from laboratory members and clinical information obtained from referring clinicians is duly acknowledged.

Funding

We like to acknowledge Indian Council of Medical Research (ICMR) for Research funding to MM and ICMR-Post doctoral fellowship (PDF) support to PG.

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Authors and Affiliations

  1. Indian Council of Medical Research (ICMR) - National Institute of Immunohaematology (NIIH), KEM Hospital, 13th floor New Multistorey Building, Parel Mumbai, Mumbai, India

    Pallavi Gaikwad, Umair Ahmed Bargir, Shweta Shinde, Amruta Dhawale, Merin George, Neha Jodhawat, Priyanka Setia, Disha Vedpathak, Aparna Dalvi, Ankita Parab, Maya Gupta, Reetika Malik Yadav, Mayuri Goriwale, Baburao Vundinti & Manisha Madkaikar

  2. Department of Pediatric Hematology Oncology, Comprehensive Thalassemia Care, PHO and BMT Centre, Borivali, Mumbai, India

    Pranoti Kini & Ratna Sharma

  3. Radiological Physics and Advisory Division, Bhabha Atomic Research Center, Trombay, Mumbai, India

    Rajesh Chaurasia, Usha Yadav, Nagesh Bhat & B. K. Sapra

  4. Department of Paediatric Intensive Care Unit, KEM Hospital, Pune, India

    Madhumati Otiv

Authors
  1. Pallavi Gaikwad
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Contributions

Pallavi Gaikwad performed the experiments and analyzed the data. Pallavi Gaikwad and Umair Bargir drafted the manuscript. Shweta Shinde, Neha Jodhawat, Priyanka Setia, Aparna Dalvi, Maya Gupta, Ankita Parab, and Mayuri Goriwale were involved in routine diagnosis and performed the flow cytometric analysis. Amruta Dhawale and Disha Vedpathak were involved in molecular work. Rajesh Chaurasia, Usha Yadav, and Merin George performed chromosomal breakage analysis while Baburao Vundinti, Nagesh Bhat, and B K Sapra supervised the chromosomal findings. Umair Bargir, Reetika Malik Yadav, Pranoti Kini, Madhumati Otiv, and Ratna Sharma helped in collecting clinical details for the entire family. Manisha Madkaikar conceptualized and approved the final draft.

Corresponding author

Correspondence to Manisha Madkaikar.

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Gaikwad, P., Bargir, U.A., Shinde, S. et al. A Clinical Conundrum with Diagnostic and Therapeutic Challenge: a Tale of Two Disorders in One Case. J Clin Immunol 43, 1891–1902 (2023). https://doi.org/10.1007/s10875-023-01553-0

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