In Response to: Pediatric Myelodysplastic Syndrome with Germline RRAS Mutation: Expanding the Phenotype of RASopathies
Nienke van EngelenIllja J. DietsDorine BrestersJ.C. van den BergenAlexander F. J. E. VranckenRoland P. KuiperMarjolijn C.J. Jongmans
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To the Editor: In response to the case report by Catts et al,1 we present a second patient with myelodysplastic syndrome (MDS) and the same de novo germline RRAS variant. The female patient was born with pulmonary subvalvular and valvular stenosis, which was surgically corrected at age 3. She had normal growth and development and attended regular education. She presented with frequent nosebleeds and menorrhagia at age 15 without probable cause. Two years later she presented with fatigue and persistent menorrhagia, she had low platelets and was diagnosed with MDS with monosomy 7. The patient was treated with an allogeneic stem cell transplantation (matched unrelated donor). During treatment she presented with pain and paralysis of the lower extremities making her confined to a wheelchair, diagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Revision of a chest computed tomography made before the stem cell transplantation showed thickened nerves, indicating pretreatment myelinization abnormalities. After treatment with intravenous immunoglobulins, the patient could walk independent, but paresis was not completely resolved. Because of the congenital heart disease, unclassified bleeding disorder and MDS, the patient was referred to a clinical geneticist who suspected Noonan syndrome (NS). Physical examination revealed no typical physical features. NS gene panel testing was negative, and SNP array analysis was normal. Trio whole exome sequencing revealed a de novo heterozygous germline RRAS variant, c.116_118dup, p.Gly39dup. This variant was confirmed by Sanger sequencing in DNA derived from a blood sample taken at age 1, excluding an MDS-related somatic mutation. A highly similar case was reported by Au et al.2 They described a 23-year-old male with subvalvular pulmonary stenosis and concurrent acute demyelinating neuropathy and MDS with monosomy 7. Genetic testing was declined by the family. The patient reported by Catts et al1 was born with craniosynostosis, mild dysmorphic features and developed MDS with monosomy 7 at age 7. A third patient with this de novo variant is a 16-year-old girl with dysmorphic facial features resembling NS and short stature. Her medical history revealed a pulmonary stenosis, delayed motor development, feeding difficulties, and acute myeloid leukemia suspected to represent a blast crisis of juvenile myelomonocytic leukemic at age 13.3 This author also reported a 51-year-old woman with an RRAS c.163G>A, p.Val55Met variant. Physical examination showed dysmorphic facial features, suggesting NS, and she developed an unspecified bone tumor during childhood. These cases show a diversity of symptoms in patients with germline RRAS variants partially overlapping with clinical symptoms of NS. In the patient reported here, the demyelinating neuropathy was striking. RRAS plays an essential role in the differentiation, proliferation, and survival of oligodendrocytes responsible for axon myelination, which might suggest a causal relation.4 Four patients developed a childhood malignancy, including three patients with a hematologic malignancy. This may indicate a higher penetrance for cancer in patients with germline RRAS variants compared with other NS (like) genes. We support the recommendation by Catts et al to add RRAS to the list of genes tested when a RASopathy is suspected. Additionally, we recommend including RRAS in pediatric cancer predisposition gene panels. Nienke van Engelen, MD* Illja Diets, PhD† Dorine Bresters, PhD* Janneke C. van den Bergen, PhD* Alexander F.J.E. Vrancken, PhD‡ Roland P. Kuiper, PhD* Marjolijn C.J. Jongmans, PhD*§ *Princess Máxima Center for Pediatric Oncology ‡Department of Neurology, Brain Centre Rudolf Magnus University Medical Centre Utrecht §Department of Genetics, University Medical Center Utrecht, Utrecht †Department of Human Genetics, Radboud University Medical Center, Nijmegen, The NetherlandsKeywords:
Noonan Syndrome
Nijmegen breakage syndrome
Compound heterozygosity
Germline mosaicism
The variation generated by germline mutation is essential for evolution, but individuals pay a steep price in the form of Mendelian disease and genetic predisposition to complex disease. Indeed, the health of a species is determined ultimately by the rate of germline mutation. Analysis of the factor IX gene in patients with hemophilia B has provided insights into the human germline mutational process. Herein, seven topics will be reviewed with emphasis on recent advances: (i) proposed mechanisms of deletions, inversions, and insertions; (ii) discordant sex ratios of mutation and associated age effects; (iii) somatic mosaicism; (iv) founder effects; (v) mutation rates; (vi) the factor IX gene as a germline mutagen test; and (vii) cancer as a possible mechanism for maintaining a constant rate of germline mutation.
Germline mosaicism
Mendelian inheritance
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Juvenile polyposis (JP) is characterized by the development of multiple hamartomatous polyps and is inherited as an autosomal dominant trait. Germline mutations of the SMAD4 gene have been reported in JP. We have previously identified three SMAD4 germline mutations in five Korean JP patients. Recently, germline mutations of the BMPR1A (ALK3) gene were reported in JP cases without SMAD4 mutations. In order to determine whether BMPR1A could be involved in the development of JP, we screened all five patients using denaturing high‐performance liquid chromatography (DHPLC) analysis. We found that one patient had a BMPR1A germline mutation without a SMAD4 mutation. This patient harbored a novel missense mutation (M470T) in exon 10. After close clinico‐pathological examination, one patient who was previously diagnosed to have JP was excluded from the JP group. In total, all four Korean JP patients had either the SMAD4 or the BMPR1A mutation, with three having SMAD4 germline mutations and one carrying a BMPR1A germline mutation.
Germline mosaicism
Mutation Testing
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We report a case of somatic APC mosaicism in an person with a clinical diagnosis of Gardner syndrome with features of attenuated polyposis coli and with an uninformative family history. In initial screening for APC mutations, the germline mutation E1573X was detected in a lower proportion than that predicted by a heterozygous mutation indicating the presence of somatic mosaicism. Pyrosequencing confirmed this hypothesis and quantified the presence of the mutation in approximately 18% of the blood lymphocytes. Mutational analysis performed in the offspring revealed a fully heterozygous E1573X mutation in 2 of the 3 individuals tested. The milder colonic phenotype exhibited by the index patient could be a consequence of the presence of the mosaicism in the colon mucosa. The detection of the mutation in other tissues and in the offspring suggests that it may have occurred early during embryogenesis, before the separation of the embryonic layers. The E1573X mutation is the most distal mutation in the APC sequence reported to date as a mosaic and, interestingly, in the context of Gardner syndrome with extensive extracolonic features. Mosaicism is an important consequence of de novo APC mutations and it should be considered in the management of apparently sporadic or de novo cases, particularly in the evaluation of the risk of siblings and offspring.
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Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes.
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Crouzon syndrome
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Mutations leading to dysregulation of the Ras/MAPK signal transduction cascade are a common cause of Noonan syndrome (NS) and play a key role in the pathogenesis of many human malignancies. To date, about 24 various RAF1 germline mutations were identified in NS. The incidence of malignancies in NS patients with RAF1 mutations has not been reported so far. However, in a few cases somatic RAF1 mutations were observed in cancer, including two described in therapy-related acute myeloid leukaemia (t-AML). We present a case of an adult female patient with Noonan syndrome and her affected mother with a rare RAF] germline mutation c.1279A>G (p.S427G), located within the highly conserved domain (CR3) of serine/threonine kinase C-RAF. Interestingly, this mutation has been reported for the first time in a patient with t-AML as a somatic change and so far has been identified in only one individual with NS phenotype and his mother. Our report presents the second familial case of Noonan syndrome due to a germline p.S427G substitution in RAF] with no occurrence of a malignant tumor. It may suggest that carrying a germline mutation in the RAF1 oncogene is not associated with an increased risk of tumor development. Since RAF1 mutations have been observed as a somatic event in many types of cancer, this report might be of importance for the genetic counselling and management of patients both with germline and somatic alterations in this gene.
Noonan Syndrome
Costello syndrome
Germline mosaicism
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Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.
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CHARGE syndrome is an autosomal dominant malformation syndrome caused by mutations in the CHD7 gene. The majority of cases are sporadic and only few familial cases have been reported. In these families, mosaicism in one parent, as well as parent- to-child transmission of a CHD7 mutation, has been described. In some further cases, germline mosaicism has been suggested. Here, we report the first case in which germline mosaicism could be demonstrated in a father of two affected children with CHARGE syndrome. The truncating mutation c.7302dupA in exon 34 of the CHD7 gene was found in both affected children but was not detected in parental lymphocytes. However, in DNA extracted from the father's spermatozoa, the c.7302dupA mutation could be identified. Furthermore, mutation analysis of DNA isolated from 59 single spermatozoa revealed that the c.7302dupA mutation occurs in 16 spermatozoa, confirming germline mosaicism in the father of the affected children. This result has a high impact for genetic counselling of the family and for their recurrence risk in further pregnancies.
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CHARGE syndrome
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