Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency

Coronin 1A belongs to a large family of actin regulatory proteins which are highly conserved, from yeast to humans (Xavier et al. 2008). The human coronin 1A gene (CORO1A) maps to chromosome 16p11.2 and consists of 11 exons. It encodes a 461 amino acid, 57 kDa actin-binding protein (Suzuki et al. 1995), and is expressed in various hematopoietic cells (Oku et al. 2003), as well as in the brain (Ahmed et al. 2007). Coronin 1A is believed to associate with polymerized actin and the actin branching facilitator actin-related protein 2/3 complex (Arp2/3) (Rybakin and Clemen 2005; Föger et al. 2006). This protein has a clear role in T cell homeostasis both in mice and human (Shiow et al. 2008), although the exact mechanism is yet to be clarified. A role for coronin 1A was also observed in macrophages (Jayachandran et al. 2007), NK (Mace and Orange 2014), and neuronal cells (Martorella et al. 2017).

Human coronin 1A deficiency was first described in a patient who presented with oral thrush, repeated respiratory infections and disseminated chicken pox after varicella vaccine. The patient was found to have 2 null mutations in CORO1A. She had T cell lymphopenia and poor T cell responses to mitogens and antigens as well as poor humoral responses (Shiow et al. 2008, 2009).

Later on, several reported cases extended the spectrum of disease associated with mutations in CORO1A (Moshous et al. 2013; Mace and Orange 2014; Stray-Pedersen et al. 2014): hypomorphic mutations in 3 siblings were associated with a predisposition to EBV-mediated B cell lymphoproliferation and transformation into lymphoma at 12, 7.5, and 14 months, respectively (Moshous et al. 2013).

An additional kindred with a compound heterozygous mutation resulting in complete loss of protein expression (Stray-Pedersen et al. 2014) presented with a late onset disease at 7 years of age, with epidermodysplasia-verruciformis-human-papilloma-virus (EV-HPV), molluscum contagiosum and mucocutaneous herpetic ulcers, as well as granulomatous tuberculoid leprosy. Abnormalities in NK cell cytotoxic function in one of these patients were identified, and shown to be related to defects in regulation of the F-actin microenvironment, thus impeding lytic granule secretion (Mace and Orange 2014). Interestingly, both asymptomatic carrier parents were found to have immune abnormalities, including CD4⁺ and NK cell lymphopenia.

The newborn screen (NBS) program for severe combined immunodeficiency (SCID) was initially implemented in Wisconsin in 2008 (Baker et al. 2010). Since then, similar programs were initiated in multiple states and world-wide (Kwan et al. 2014; Kanegae et al. 2016; Blom et al. 2017). The NBS program in Ontario, Canada, has been successfully implemented since 2013 (Cross 2013). The basis behind the successful NBS for SCID is the T cell receptor excision circles (TREC) assay (Accetta Pedersen et al. 2011). This assay involves an RT-PCR reaction to detect a TREC, which is a physiological byproduct of the V(D)J recombination process occurring in maturing thymocytes. Since TRECs do not replicate, they are a good biomarker of thymic output.

Several studies have retrospectively examined the yield of the TREC assay as a NBS for classical SCID as well as other conditions associated with T cell lymphopenia (Kwan et al. 2014; van der Spek et al. 2015). Low or undetectable TREC levels were found to have an excellent yield in the diagnosis of “typical SCID” (defined as autologous T cell count <500 cells/μL and response to PHA proliferation of <10% of normal (Roifman et al. 2012)), as well as some cases of combined immunodeficiency (CID) (autologous T cell count of >500 cells/μL and reduced response to PHA proliferation). While prematurity is a common reason for low TREC numbers, repeating the test at a later age prevents unnecessary investigations. Pre- and perinatal medication use can also result in a false positive test, thus requiring prudence in interpretation of the test. Other causes for T cell lymphopenia included various syndromes, such as Di George syndrome/22q11.2 chromosome deletion, trisomy 21, trisomy 18, ataxia telangiectasia, CHARGE (coloboma, heart defect, atresia choanae, retarded growth and development, genital and ear abnormalities) syndrome and various less common entities. Importantly, identification of these syndromes, including CID, by NBS programs is not uniform. Depending of the cutoff for reporting of low TREC levels, variable numbers of infants are recognized as having idiopathic T cell lymphopenia, and required continued follow up and investigations for combined immunodeficiency.

We report here a case of coronin 1A deficiency caused by a novel homozygous mutation. The infant was detected to have profound T cell deficiency by TREC-based NBS.

The patient is a 14 month old female, born at term to a single mother of African descent. Perinatal history was unremarkable. There is no known consanguinity in the family. The patient’s mother has a history of recurrent vaginal yeast infections and neutropenia. The patient was found to have low TREC values during NBS.

We report here the first coronin 1A deficient patient detected by positive NBS for SCID. This patient presented with leukopenia and neutropenia, but is currently doing clinically well at 14 months of age with no severe or recurrent infections. Previous reports show great variability in clinical presentations, ranging from patients presenting as severe combined immunodeficiency and severe vaccine-associated varicella infection (Shiow et al. 2008), through patients presenting with EBV related lymphoproliferation at a young age (Moshous et al. 2013) and a yet later onset of disease, at 7 years of age (Stray-Pedersen et al. 2014).

All patients reported thus far had T cell lymphopenia (Shiow et al. 2008; Moshous et al. 2013; Stray-Pedersen et al. 2014). Another feature common to most patients is the severe reduction in CD45Ra⁺ naïve T cells (Moshous et al. 2013; Moshous and de Villartay 2014; Stray-Pedersen et al. 2014) suggesting a role of coronin 1A in mature T cell survival or thymocyte development. However, B and NK cell counts, T cell responses to mitogen and antigens, as well as humoral function are all variable among patients (Shiow et al. 2008; Moshous et al. 2013; Mace and Orange 2014; Stray-Pedersen et al. 2014). One patient (Mace and Orange 2014) was described to have abnormalities in NK cytotoxic function.

A genotype–phenotype correlation was postulated previously (Moshous and de Villartay 2014). However, the finding of a kindred with late onset disease and a null homozygous mutation (Stray-Pedersen et al. 2014) make any assumptions on such a correlation difficult.

Early studies on coronin 1A in phagocytes indicated an important role in the rearrangement of actin and regulation of p40^phox, a component of the NADPH oxidase (Grogan et al. 1997). Defective NADPH oxidase function, which is responsible for production of microbicidal superoxide and reactive oxygen species, leads to chronic granulomatous disease. Binding studies show that coronin 1A associates with the C-terminal region of p40^phox. In the absence of its binding partner, coronin 1A and F-actin fail to rearrange during phagocytosis. Indeed, coronin 1A has also been shown to regulate other aspects of neutrophil biology, including trafficking and apoptosis. In murine models of coronin 1A deficiency, aberrant accumulation of lymphocyte-function associated antigen 1, needed to transition neutrophils from being firmly adherent to migratory, impairs leukocyte movement to sites of inflammation (Pick et al. 2017). Coronin 1A has also been identified by proteomic analysis to be involved in neutrophil apoptosis (Moriceau et al. 2009). Overexpression was associated with a lower rate of apoptosis due in part to delayed phosphatidylserine externalization, as shown in patients with cystic fibrosis. Functional analysis of neutrophils was not performed in our patient, however, one could hypothesize that the loss of coronin 1A expression may have resulted in dysregulated apoptosis and innate defense against infections.

We report here the first case of coronin 1A deficiency presenting as a clinically asymptomatic positive NBS for SCID. As the newborn TREC assay for screening for SCID is gaining worldwide prevalence, we might see an increase in diagnoses of coronin 1A as well as other combined immunodeficiencies and a broadening of the clinical spectrum of these conditions. Most combined immunodeficiencies are not diagnosed by the various NBS programs, whose purpose is to provide timely diagnosis and treatment only to the most severe cases of T cell deficiencies. As combined immunodeficiencies have a wide spectrum of disease severity, often within the same genetic entity, one would expect for the more severe presentations within the spectrum of disease to be diagnosed by low newborn TREC results. Whether this early recognition will result in an improved prognosis remains to be proven. The cutoff of a specific NBS program for reporting abnormal results, and the algorithm for investigating these results, also affect the capture rate of non-SCID T cell lymphopenias. This must be weighed against the resources in the specific program for follow up and investigation of these newborns.

Our patient presented with severe neutropenia along with her lymphopenia. This finding, which is also consistent in her asymptomatic mother, has not been previously reported in coronin 1A deficiency. Although coronin 1A is known to function as a regulator of cytoskeleton, it was not reported to affect neutrophil function (Combaluzier and Pieters 2009).

We hereby report the first case of coronin 1A deficiency presenting in a well newborn as part of the NBS program. Coronin 1A is a rare combined immunodeficiency, and the few cases reported in the literature had a variable although detrimental clinical course. As our patient is currently well, we are confronted with one of the challenges posed by early diagnosis of rare diseases, i.e., the inability of predicting prognosis, and thus the difficulty in recommending a potentially risky procedure, such as HSCT.