Recessive Mutations in MCM4/PRKDC Cause a Novel Syndrome
Background A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event.
Methods Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives.
Results A locus for the syndrome was identified at 8p11.21–q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients.
Conclusion Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.
Members of three clans from the Irish Traveller population have presented to a variety of clinical specialists, including paediatric endocrinologists, haematologists and geneticists, with intrauterine growth retardation (IUGR) and failure to thrive (FTT). All affected individuals from the first presenting family (pedigree 1) had clinodactyly, some had episodes of hypoglycaemia, and those tested had delayed bone age. Some patients had relative macrocephaly, with head circumference measurement on the 3rd centile, and height and weight below the 3rd centile. In others, all three variables were below the 3rd centile.
Members of a second clan (pedigree 2) from the Irish Traveller population presented to endocrinologists with IUGR, FTT, hypoglycaemia and clinodactyly. When investigated, the affected children were found to develop hyperpigmentation (after 2 years of age) and increased adrenocorticotropin hormone (ACTH) levels over time (mean age 5 years), with low–normal cortisol concentrations, confirming a diagnosis of familial glucocorticoid deficiency (FGD). However, symptomatic presentation of FGD was later than normal for the condition. At initial diagnosis, the patients had a tanned appearance typical of FGD. Most patients who were regularly taking their hydrocortisone had normal skin colouring, while those who were not compliant with medication continued to have a tanned appearance. Because of a history of recurrent infections, some of the children from pedigree 2 were investigated for disordered immunological function, which revealed low levels of natural killer (NK) cells and evidence of a DNA repair disorder. Clinical features of the DNA repair phenotype in members of this clan were described by Eidenschenk et al. Members of a third clan (pedigree 3) were referred to clinical geneticists with suspected Russell–Silver syndrome, but a diagnosis of FGD was made on the basis of the development of increased pigmentation and subsequent biochemical investigations.
As some members of the original clan (pedigree 1) were later found to have high ACTH levels, we postulated that the NK cell deficiency, DNA repair disorder and FGD were the result of a single recessive genetic event. We proceeded to test members of all the clans for the three different phenotypes and found that those with a diagnosis of FGD also had low NK cells, and some showed defective DNA repair. The DNA repair disorder was classified as mosaic Fanconi's anaemia (FA), but the patients do not have the typical mosaic FA test result or the expected clinical features of the disorder. In mosaic FA, patients have two subpopulations of cells, one of which is hypersensitive to cross-linking agents (diepoxybutane (DEB)), while the other behaves normally in response to these agents. Upon testing, patients with mosaic FA have some cells with high levels of DNA damage and others that are completely normal. However, often the patients in this study have a relatively low level of DNA damage in a minority of cells. The observed chromosome breakage is greater than that expected from a healthy individual but less than that of mosaic FA.
This study involves 10 individuals from three consanguineous Irish Traveller families who were diagnosed with a combination of an NK cell deficiency, mosaic FA and FGD (figure 1A,B,C). Many of these children would not have been investigated and diagnosed were it not for their family history. Clinical and laboratory details of the 10 patients are discussed (Table 1 and online supplementary material). Details of the presentation and endocrine findings of some of these patients were previously described by O' Riordan and colleagues. We performed single-nucleotide polymorphism (SNP) homozygosity mapping and targeted next-generation sequencing to identify the underlying risk gene in these families.
(Enlarge Image)
Figure 1.
Pedigrees of Irish Traveller families presenting with a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. Individuals from whom DNA was available are marked with a *. (A) Pedigree 1 includes five affected individuals initially assessed for query Russell–Silver syndrome. DNA from five affected and eight unaffected individuals was available for homozygosity mapping. Patients III:11 and IV:4 were also diagnosed as having a mild mosaic form of Fanconi's anaemia (FA). Patient IV:9 has a natural killer (NK) cell deficiency, but the results of the FA test are of unclear significance. Patient IV:10 was diagnosed as having an NK cell deficiency. (B) Pedigree 2 includes eight affected family members. One affected individual (IV:16) died aged 11 years from bronchiectasis. DNA was available for homozygosity mapping from four affected and three unaffected individuals. All of the affected individuals were diagnosed as having mosaic FA (IV:19 has classic FA), an NK cell deficiency and familial glucocorticoid deficiency (FGD). (C) Pedigree 3 includes one affected proband initially suspected of having Russell–Silver syndrome. Further investigation led to a diagnosis of an NK cell deficiency and FGD. (D) Single nucleotide polymorphism homozygosity mapping using the HomozygosityMapper programme identified a single candidate locus at 8p11.21–q11.22 (chromosome 8:40,802,495–51,349,159), which includes 34 positional candidate genes.
Abstract and Introduction
Abstract
Background A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event.
Methods Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives.
Results A locus for the syndrome was identified at 8p11.21–q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients.
Conclusion Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.
Introduction
Members of three clans from the Irish Traveller population have presented to a variety of clinical specialists, including paediatric endocrinologists, haematologists and geneticists, with intrauterine growth retardation (IUGR) and failure to thrive (FTT). All affected individuals from the first presenting family (pedigree 1) had clinodactyly, some had episodes of hypoglycaemia, and those tested had delayed bone age. Some patients had relative macrocephaly, with head circumference measurement on the 3rd centile, and height and weight below the 3rd centile. In others, all three variables were below the 3rd centile.
Members of a second clan (pedigree 2) from the Irish Traveller population presented to endocrinologists with IUGR, FTT, hypoglycaemia and clinodactyly. When investigated, the affected children were found to develop hyperpigmentation (after 2 years of age) and increased adrenocorticotropin hormone (ACTH) levels over time (mean age 5 years), with low–normal cortisol concentrations, confirming a diagnosis of familial glucocorticoid deficiency (FGD). However, symptomatic presentation of FGD was later than normal for the condition. At initial diagnosis, the patients had a tanned appearance typical of FGD. Most patients who were regularly taking their hydrocortisone had normal skin colouring, while those who were not compliant with medication continued to have a tanned appearance. Because of a history of recurrent infections, some of the children from pedigree 2 were investigated for disordered immunological function, which revealed low levels of natural killer (NK) cells and evidence of a DNA repair disorder. Clinical features of the DNA repair phenotype in members of this clan were described by Eidenschenk et al. Members of a third clan (pedigree 3) were referred to clinical geneticists with suspected Russell–Silver syndrome, but a diagnosis of FGD was made on the basis of the development of increased pigmentation and subsequent biochemical investigations.
As some members of the original clan (pedigree 1) were later found to have high ACTH levels, we postulated that the NK cell deficiency, DNA repair disorder and FGD were the result of a single recessive genetic event. We proceeded to test members of all the clans for the three different phenotypes and found that those with a diagnosis of FGD also had low NK cells, and some showed defective DNA repair. The DNA repair disorder was classified as mosaic Fanconi's anaemia (FA), but the patients do not have the typical mosaic FA test result or the expected clinical features of the disorder. In mosaic FA, patients have two subpopulations of cells, one of which is hypersensitive to cross-linking agents (diepoxybutane (DEB)), while the other behaves normally in response to these agents. Upon testing, patients with mosaic FA have some cells with high levels of DNA damage and others that are completely normal. However, often the patients in this study have a relatively low level of DNA damage in a minority of cells. The observed chromosome breakage is greater than that expected from a healthy individual but less than that of mosaic FA.
This study involves 10 individuals from three consanguineous Irish Traveller families who were diagnosed with a combination of an NK cell deficiency, mosaic FA and FGD (figure 1A,B,C). Many of these children would not have been investigated and diagnosed were it not for their family history. Clinical and laboratory details of the 10 patients are discussed (Table 1 and online supplementary material). Details of the presentation and endocrine findings of some of these patients were previously described by O' Riordan and colleagues. We performed single-nucleotide polymorphism (SNP) homozygosity mapping and targeted next-generation sequencing to identify the underlying risk gene in these families.
(Enlarge Image)
Figure 1.
Pedigrees of Irish Traveller families presenting with a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. Individuals from whom DNA was available are marked with a *. (A) Pedigree 1 includes five affected individuals initially assessed for query Russell–Silver syndrome. DNA from five affected and eight unaffected individuals was available for homozygosity mapping. Patients III:11 and IV:4 were also diagnosed as having a mild mosaic form of Fanconi's anaemia (FA). Patient IV:9 has a natural killer (NK) cell deficiency, but the results of the FA test are of unclear significance. Patient IV:10 was diagnosed as having an NK cell deficiency. (B) Pedigree 2 includes eight affected family members. One affected individual (IV:16) died aged 11 years from bronchiectasis. DNA was available for homozygosity mapping from four affected and three unaffected individuals. All of the affected individuals were diagnosed as having mosaic FA (IV:19 has classic FA), an NK cell deficiency and familial glucocorticoid deficiency (FGD). (C) Pedigree 3 includes one affected proband initially suspected of having Russell–Silver syndrome. Further investigation led to a diagnosis of an NK cell deficiency and FGD. (D) Single nucleotide polymorphism homozygosity mapping using the HomozygosityMapper programme identified a single candidate locus at 8p11.21–q11.22 (chromosome 8:40,802,495–51,349,159), which includes 34 positional candidate genes.
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