The University of Chicago Genetic Services Laboratories

Transcription

1 The University of Chicago tic Services Laboratories 5841 S. Maryland Ave., Rm. G701, MC 0077, Chicago, Illinois dnatesting.uchicago.edu CLIA #: 14D CAP #: Next ration Sequencing Panel for Inherited Bone Marrow Failure Syndromes : Inherited bone marrow failure syndromes are a diverse group of rare disorders associated with insufficient production of blood cells and cancer predisposition [1]. Bone marrow failure can affect all three hematopoietic cell lineages, or be restricted to one particular lineage [2]. Aplastic anemia can also be caused by other disorders, including paroxysomal nocturnal hemoglobinuria, myelodysplastic syndrome and acute myeloid leukemia [1]. Our Comprehensive Inherited Bone Marrow Failure Panel includes sequence analysis of all 49 genes listed below, and deletion/duplication analysis of the 30 genes in bold below. Our Inherited Bone Marrow Failure Sequencing Panel includes sequence analysis of all 49 genes listed below. Our Inherited Bone Marrow Failure Deletion/Duplication Panel includes deletion/duplication analysis of all 30 genes listed in bold below. Dyskeratosis Congenita Inherited Bone Marrow Failure s Fanconi Anemia Diamond- Blackfan Anemia Severe Congenital Neutropenia Other CTC1 BRCA2 (FANCD1) FANCI RPL11 CSF3R GATA2 DKC1 BRIP1 (FANCJ) FANCL RPL35A ELANE (ELA2) MPL NOP10 (NOLA3) ERCC4 (FANCQ) FANCM RPL5 G6PC3 RBM8A NHP2 FANCA PALB2 (FANCN) RPS10 GFI1 RUNX1 RTEL1 FANCB RAD51C (FANCO) RPS19 HAX1 SBDS TERC FANCC SLX4 (FANCP) RPS24 VPS45 SBF2 TERT FANCD2 XRCC2 RPS26 WAS SRP72 WRAP53 (TCAB1) FANCE RPS7 TINF2 USB1 (C16orf57) FANCF FANCG Dyskeratosis Congenita Dyskeratosis congenita (DC) is a highly heterogeneous disorder characterized by abnormal skin pigmentation, nail dystrophy and oral leukoplakia (mucosal keratosis appearing as white patches in the oral cavity) [3]. This classic triad of findings is present in 80-90% of affected individuals [4]. Bone marrow failure is present in approximately 85% of cases [4]. Other disease manifestations can include epiphora (excessive tear production), intellectual disability, pulmonary fibrosis, abnormal pulmonary vasculature, tooth loss or decay, premature hair loss or greying, liver disease, osteoporosis, and deafness [4]. Dyskeratosis congenita is commonly associated with shortened telomeres [4]. Anticipation may be observed in affected families, and is thought to be due to the inheritance of shortened telomeres from an affected parent [4]. DC can be inherited in either an autosomal dominant, autosomal recessive or X-linked manner, depending on the causative gene. USB1 (C16orf57) Walne et al. (2010) identified homozygous mutations in the USB1 (C16orf57) gene in 6 out of 132 families with dyskeratosis congenita (DC) [5]. DC has previously been associated with short telomeres, however patients with USB1 mutations and DC were found to have normal length telomeres [5]. Mutations in the USB1 gene have also been described in individuals with poikiloderma with neutropenia (PN), which is characterized by poikilodermatous rash (patchy skin discoloration), noncyclical neutropenia, small stature, pachyonychia, and pulmonary disease [6].

2 CTC1 Keller et al. (2012) identified compound heterozygous mutations in CTC1 in a patient with DC [7]. The CTC1 gene is also associated with Coats syndrome, which is characterized by bilateral exudative retinopathy, intracranial calcifications and cysts, premature hair greying, osteoporosis and anemia [8]. DKC1 Mutations in the X-linked DKC1 gene are the most common cause of DC [9]. Age of onset and severity of symptoms is highly variable, but affected males typically present in the first decade of life, and typically die in their twenties due to complications from bone marrow failure [9]. Many mutations occur de novo. Female heterozygous carriers are typically asymptomatic [9]. NOP10 (NOLA3) A homozygous mutation in NOP10 was identified in 3 individuals with DC in a consanguineous family [10]. All three individuals had the mucocutaneous features of DC, one individual also developed bone marrow failure [10]. NHP2 Biallelic mutations in NHP2 have been described in two patients with DC [11]. RTEL1 Both dominant and recessive mutations in the RTEL1 gene have been associated with Hoyeraal Hreidarsson syndrome, a clinically severe variant of DC with cerebellar hypoplasia, severe immunodeficiency, enteropathy, and intrauterine growth retardation [12]. Anticipation has been described in one family where two affected males inherited a heterozygous mutation from a clinically unaffected female with short telomeres [12]. TERC Heterozygous mutations in the TERC gene account for approximately 4% of all cases of DC [9]. Anticipation has been observed in families with TERC-associated DC, with increased disease severity and earlier age of onset seen with successive affected generations [9]. TERT Heterozygous mutations in TERT have been associated with DC or aplastic anemia [9]. Penetrance of these mutations appears to be reduced, with some individuals being asymptomatic [9]. Variable expressivity has also been described, with some individuals being mildly affected [9]. WRAP53 Biallelic mutations in TCAB1 have been described in individuals with classical DC from two different (TCAB1) TINF2 families [13]. Dominant mutations in TINF2 have been described in patients with DC [14]. Both inherited and de novo mutations have also been described [14, 15]. Fanconi Anemia Fanconi anemia (FA) is a chromosomal instability disorder associated congenital anomalies, progressive bone marrow failure, and cancer predisposition [16]. The most commonly described anomalies include thumb and radial bone abnormalities, short stature and skin hyperpigmentation [16]. Some patients lack these characteristic physical features and first present with bone marrow failure or cancer [17]. Associated cancers include acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and solid tumors of the head, neck, skin, gastrointestinal tract and genital tract [16]. The majority of cases of FA are inherited in an autosomal recessive manner. Mutations in the FANCB gene are inherited in an X-linked manner. BRCA2 Homozygous or compound heterozygous mutations in BRCA2 are associated with FA (FANCD1) complementation group D1. BRCA2 mutations are associated with early-onset leukemia and solid tumors, and a high rate of spontaneous chromosome aberration compared to other types of FA [18, 19]. Heterozygous mutations in BRCA2 are associated with hereditary breast and ovarian cancer [20]. BRIP1 (FANCJ) FA complementation group J is associated with biallelic mutations in the BRIP1 gene [21]. There is some evidence that heterozygous BRIP1 mutations may be associated with increased breast cancer susceptibility [22]. ERCC4 (FANCQ) FA complementation group Q is associated with biallelic ERCC4 mutations [23]. ERCC4 mutations can also be associated with xeroderma pigmentosa [24]. FANCA Biallelic FANCA mutations are associated with FA complementation group A [25]. Patients with mutations associated with no FANCA protein production may have earlier onset anemia and higher risk of leukemia, compared with patients with production of an abnormal FANCA protein [25]. FANCB Mutations in the X-linked FANCB are associated with FA complementation group B. Affected patients typically have multiple malformations, including a ventriculomegaly or hydrocephalus, bilateral radial defects, vertebral defects, and renal agenesis [26]. An estimated 50% of affected males do not survive the perinatal period; heterozygous females are typically unaffected and exhibit skewed X-inactivation [26]. FANCC FA complementation group C is associated with biallelic mutations in FANCC. A founder mutation in FANCC exists in the Ashkenazi Jewish population, and has a carrier frequency of 1 in 100 [27]. Biallelic mutations in FANCD2 are associated with FA complementation group D2, and account for FANCD2 approximately 3-6% of all cases of FA [28]. Patients with FANCD2 mutations frequently have congenital malformations, and have earlier onset hematological manifestations compared FA cases overall [28]. FANCE Homozygous mutations in FANCE have previously been identified in 2 Turkish patients and 1 Bangladeshi patient with FA complementation group E [29]. FANCF FA complementation group F is caused by homozygous or compound heterozygous mutations in the FANCF gene [30].

3 Biallelic FANCG mutations are associated with FA complementation group G. FANCG mutations are FANCG typically associated with more severe cytopenia and a higher risk of leukemia than is observed with cases of FA in general [25]. FANCI FA complementation group I is caused by homozygous or compound heterozygous mutations in the FANCI gene [31]. FANCL A patient with FA complementation group L and compound heterozygous mutations in FANCL has previously been described [32]. FANCM Compound heterozygous mutations in the FANCM gene have been described in a patient with FA complementation group M [33]. PALB2 (FANCN) FA complementation group N has been associated with compound heterozygous mutations in PALB2. Heterozygous mutations in PALB2 have been associated with increased susceptibility to breast cancer [34]. RAD51C A homozygous mutation in RAD51C has previously been described in a family with FA (FANCO) complementation group O [35]. Heterozygous mutations in this gene have been associated with breast cancer predisposition [36]. SLX4 (FANCP) FA complementation group P has been associated with either homozygous or compound heterozygous mutations in the SLX4 gene [37]. XRCC2 A homozygous truncating mutation was identified in the XRCC2 gene in a patient with FA [38]. Severe Congenital Neutropenia (SCN) Severe congenital neutropenia (SCN) is characterized by severe neutropenia at birth [39]. Bone marrow exhibits arrest of neutrophil maturation at the promyelocyte or myelocyte stage of development [39]. By age 6 months, 90% of patients with SCN develop bacterial infections such as skin or deep tissue abscesses, oral ulcers and pneumonia [39]. Despite improvements in therapy there remains a 12% risk of death due to sepsis by age 15 years [39]. Patients with SCN also have an increased risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with a hazard rate of 2% per year [39]. SCN can be inherited in either an autosomal dominant, autosomal recessive or X-linked manner, depending on the causative gene. CSF3R Biallelic loss-of-function mutations in CSF3R have been described in patients with SCN [40]. Plo et al. (2009) identified a heterozygous activating mutation in CSF3R in a family with dominantly inherited chronic neutropenia [41]. One affected family member also developed MDS. ELANE (ELA2) Heterozygous mutations in the ELANE gene are responsible for the majority of cases of SCN [42]. ELANE can also be associated with cyclic neutropenia [42]. To clear phenotype-genotype correlations exist, and there is significant overlap between predicted severity of the mutation and the clinical phenotype [42]. G6PC3 GFI1 HAX1 VPS45 WAS Biallelic mutations in G6PC3 have been associated with SCN type 4 [43]. Patients with G6PC3 deficiency commonly present with congenital anomalies including cardiac anomalies, urogenital malformations and venous angietasia [43]. Alangari et al. (2013) described a consanguineous family where affected individuals presented with either SCN or cyclic neutropenia [43]. Dominant-negative mutations in GFI1 have been associated with SCN [44]. GFI1 mutations have also been identified in patients with nonimmune chronic idiopathic neutropenia of adults [45]. Biallelic mutations in HAX1 account for 15% of cases of SCN [44]. A proportion of patients with HAX1- associated SCN also develop neurological disease such as cognitive impairment, developmental delay, and epilepsy [44]. Stepensky et al. (2013) identified homozygous mutations in VPS45 in patients with SCN [46]. Affected individuals developed neutropenia, thrombasthenia, myelofibrosis and progressive bone marrow failure [46]. Activating mutations in the X-linked WAS gene are associated with SCN and lmyphopenia [44]. Loss of function mutations in WAS have been associated with Wiskott-Aldrich syndrome, associated with immunodeficiency, eczema, microthromobocytopenia, and susceptibility to malignant lymphoma [44]. Diamond-Blackfan Anemia (DBA) Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia disorder associated with reduced or absent erythroid precursors in bone marrow, macrocytic anemia and reticulocytopenia [39]. Approximately 30% of cases have growth retardation and 50% have congenital anomalies, which may include thumb anomalies, congenital heart defects and midline facial defects such as cleft palate and hypertelorism [39]. Patients have an increased risk of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors such as osteogenic sarcoma [39]. The cumulative incidence of solid tumors or leukemia is 22% by age 46 [47]. DBA is a genetically heterogeneous condition, with the currently known genes accounting for 50-70% of cases [39]. All the DBA genes included on this panel are inherited in an autosomal dominant manner. An estimated 55-60% of cases are caused by de novo mutations; DBA has variable expressivity and penetrance is incomplete.

4 RPL11 RPL35A RPL5 RPS10 Heterozygous mutations in RPL11 are associated with DBA type 7. In terms of observed congenital malformations, mutations in RPL11 are predominantly associated with isolated thumb defects [48]. Mutations in RPL35A have been identified in both familial and sporadic cases of DBA type 5. In one familial case, some individuals were found to have subclinical DBA with macrocytic anemia [49]. DBA type 6, caused by heterozygous mutations in RPL5, is typically associated with multiple physical anomalies, including craniofacial, thumb and cardiac anomalies [48]. RPS10 mutations are associated with DBA type 6, and are estimated to account for 2.6% of all DBA cases [50]. RPS19 Mutations in the RPS19 gene account for an estimated 24% of all DBA cases overall [51]. RPS24 RPS24 mutations are associated with DBA type 3, and account for an estimated 2% of DBA cases [52]. Both sporadic and familial mutations have been described [52]. RPS26 RPS7 Mutations in RPS26 are associated with DBA type 10, and account for an estimated 6.4% of DBA cases overall. Based on available data from a limited number of cases, physical malformations appear to be rare in patients with RPS26 mutations [50]. RPS7 has been associated with DBA type 8 [53]. At least one individual with no associated physical anomalies has been described [48]. GATA2 MPL RBM8A RUNX1 SBDS SBF2 SRP72 Other tic Causes of Bone Marrow Failure Zhang et al (2014) identified germline mutations in five out of 71 subjects with idiopathic bone marrow failure or myelodysplastic syndrome [54]. These patients did not have additional features associated with other GATA2 disorders, Emberger syndrome and MonoMac. Biallelic mutations in the MPL gene have been associated with congenital amegakaryocytic thrombocytopenia (CAMT), which typically presents with thrombocytopenia during infancy, but can also present as bone marrow failure without a specific history of thrombocytopenia [16]. The RBM8A gene is associated with thrombocytopenia-absent radius (TAR) syndrome, a rare autosomal recessive disorder [55]. Affected individuals have severe thrombocytopenia at birth, and bilateral radial hypoplasia or aplasia, with preservation of thumbs [55]. The majority of patients with TAR are heterozygous for a 200kb deletion at 1q21.1 which encompasses the RBM8A gene. In patients who carry the 200kb deletion, the remaining RBM8A allele is typically hypomorphic due the presence of 1 of 2 known low frequency SNPs, either in the 5 UTR or in the first intron. Zhang et al (2014) identified a truncating germline mutation in RUNX1 in a patient with myelodysplastic syndrome, including neutropenia and thrombocytopenia [54]. Additional clinical findings included Chiari I malformation, scoliosis, myopathy, and chronic obstructive pulmonary disease. Homozygous or compound heterozygous mutations in SBDS are associated with Shwachman- Diamond syndrome, which is characterized by short stature, exocrine pancreatic insufficiency, and bone marrow dysfunction [56]. Hematologic findings can include intermittent neutropenia, anemia, increased fetal hemoglobin levels, thrombocytopenia and aplastic anemia [56]. There is an increased risk of malignant transformation, including a risk of AML [56]. Heterozygous mutations in SBDS have been associated with aplastic anemia [57]. A homozygous mutation in the SBF2 gene has been described in a family with congenital thrombocytopenia and mucocutaneous bleeding [58]. Homozygous mutations in SBF2 have also been associated with Charcot-Marie-Tooth disease type 4B2 [59]. Kirwan et al. (2012) identified a mutation in SRP72 in a family with autosomal dominant aplastic anemia/myelodysplasia and congenital deafness[60]. An additional mutation was identified in a family with autosomal dominant myelodysplasia [60]. Test methods: Comprehensive sequence coverage of the coding regions and splice junctions of all genes in this panel is performed. Targets of interests are enriched and prepared for sequencing using the Agilent SureSelect system. Sequencing is performed using Illumina technology and reads are aligned to the reference sequence. Variants are identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors. All novel and/or potentially pathogenic variants are confirmed by Sanger sequencing. The technical sensitivity of this test is estimated to be >99% for single nucleotide changes and insertions and deletions of less than 20 bp. Deletion/duplication analysis of the panel genes is performed by oligonucleotide array-cgh. Partial exonic copy number changes and rearrangements of less than 400 bp may not be detected by array-cgh. Array-CGH will not detect low-level mosaicism, balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype. The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

5 Comprehensive Bone Marrow Failure Panel (sequence analysis of 49 genes, deletion/duplication analysis of 30 genes) Sample specifications: 3 to10 cc of blood in a purple top (EDTA) tube. NOTE: blood samples are not accepted if patient has a history of MDS or leukemia. Please send 2 T-25 flasks of cultured skin fibroblasts instead. Cost: $6000 CPT codes: Turn-around time: 6 weeks Note: We cannot bill insurance for the Inherited Bone Marrow Failure Sequencing panel Inherited Bone Marrow Failure Sequencing Panel (sequence analysis of 49 genes) Sample specifications: 3 to10 cc of blood in a purple top (EDTA) tube. NOTE: blood samples are not accepted if patient has a history of MDS or leukemia. Please send 2 T-25 flasks of cultured skin fibroblasts instead. Cost: $4000 CPT codes: Turn-around time: 6 weeks Note: We cannot bill insurance for the Inherited Bone Marrow Failure Sequencing panel Inherited Bone Marrow Failure Deletion/Duplication Panel (sequence analysis of 30 genes) Sample specifications: 3 to10 cc of blood in a purple top (EDTA) tube. NOTE: blood samples are not accepted if patient has a history of MDS or leukemia. Please send 2 T-25 flasks of cultured skin fibroblasts instead. Cost: $2500 CPT codes: Turn-around time: 6 weeks Results: Results, along with an interpretive report, are faxed to the referring physician as soon as they are completed. One report will be issued for the entire Inherited Bone Marrow Sequencing Panel. All abnormal results are reported by telephone. References: 1. Shimamura, A. and B.P. Alter, Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev, (3): p Parikh, S. and M. Bessler, Recent insights into inherited bone marrow failure syndromes. Curr Opin Pediatr, (1): p Sakaguchi, H., K. Nakanishi, and S. Kojima, Inherited bone marrow failure syndromes in Int J Hematol, (1): p Kirwan, M. and I. Dokal, Dyskeratosis congenita, stem cells and telomeres. Biochim Biophys Acta, (4): p Walne, A.J., et al., Mutations in C16orf57 and normal-length telomeres unify a subset of patients with dyskeratosis congenita, poikiloderma with neutropenia and Rothmund-Thomson syndrome. Hum Mol t, (22): p Wang, L.L., et al., Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-navajo patients. Am J Med t A, A(3): p Keller, R.B., et al., CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer, (2): p Armanios, M., An emerging role for the conserved telomere component 1 (CTC1) in human genetic disease. Pediatr Blood Cancer, (2): p Mason, P.J. and M. Bessler, The genetics of dyskeratosis congenita. Cancer t, (12): p Walne, A.J., et al., tic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomeraseassociated protein NOP10. Hum Mol t, (13): p Vulliamy, T., et al., Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A, (23): p Ballew, B.J., et al., Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum t, (4): p Zhong, F., et al., Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. s Dev, (1): p Savage, S.A., et al., TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum t, (2): p Tsangaris, E., et al., Ataxia and pancytopenia caused by a mutation in TINF2. Hum t, (5): p Khincha, P.P. and S.A. Savage, Genomic characterization of the inherited bone marrow failure syndromes. Semin Hematol, (4): p Chirnomas, S.D. and G.M. Kupfer, The inherited bone marrow failure syndromes. Pediatr Clin North Am, (6): p Hirsch, B., et al., Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood, (7): p Wagner, J.E., et al., Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood, (8): p Martin, A.M., et al., Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic. J Clin Oncol, (8): p Levitus, M., et al., The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat t, (9): p Seal, S., et al., Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat t, (11): p Bogliolo, M., et al., Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am J Hum t, (5): p Cleaver, J.E., et al., A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat, (1): p Faivre, L., et al., Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood, (13): p

6 26. McCauley, J., et al., X-linked VACTERL with hydrocephalus syndrome: further delineation of the phenotype caused by FANCB mutations. Am J Med t A, A(10): p Kutler, D.I. and A.D. Auerbach, Fanconi anemia in Ashkenazi Jews. Fam Cancer, (3-4): p Kalb, R., et al., Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Am J Hum t, (5): p de Winter, J.P., et al., Isolation of a cdna representing the Fanconi anemia complementation group E gene. Am J Hum t, (5): p de Winter, J.P., et al., The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nat t, (1): p Dorsman, J.C., et al., Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol, (3): p Ali, A.M., et al., Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. Hum Mutat, (7): p. E Meetei, A.R., et al., A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat t, (9): p Poumpouridou, N. and C. Kroupis, Hereditary breast cancer: beyond BRCA genetic analysis; PALB2 emerges. Clin Chem Lab Med, (3): p Vaz, F., et al., Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat t, (5): p Golmard, L., et al., Germline mutation in the RAD51B gene confers predisposition to breast cancer. BMC Cancer, : p Stoepker, C., et al., SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat t, (2): p Shamseldin, H.E., M. Elfaki, and F.S. Alkuraya, Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. J Med t, (3): p Wilson, D.B., et al., Inherited bone marrow failure syndromes in adolescents and young adults. Ann Med, 2014: p Triot, A., et al., Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood, Plo, I., et al., An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med, (8): p Germeshausen, M., et al., The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat, (6): p Alangari, A.A., et al., A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family. J Clin Immunol, (8): p Boztug, K. and C. Klein, tics and pathophysiology of severe congenital neutropenia syndromes unrelated to neutrophil elastase. Hematol Oncol Clin North Am, (1): p , vii. 45. Person, R.E., et al., Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat t, (3): p Stepensky, P., et al., The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy. Blood, (25): p Vlachos, A., et al., Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood, (16): p Gazda, H.T., et al., Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum t, (6): p Farrar, J.E., et al., Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood, (5): p Doherty, L., et al., Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum t, (2): p Willig, T.N., et al., Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood, (12): p Gazda, H.T., et al., Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum t, (6): p Gerrard, G., et al., Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond- Blackfan anaemia. Br J Haematol, (4): p Zhang, M.Y., et al., Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. Haematologica, Yassaee, V.R., et al., A new approach for molecular diagnosis of TAR syndrome. Clin Biochem, Kuijpers, T.W., et al., Hematologic abnormalities in Shwachman Diamond syndrome: lack of genotype-phenotype relationship. Blood, (1): p Calado, R.T., et al., Mutations in the SBDS gene in acquired aplastic anemia. Blood, (4): p Abuzenadah, A.M., et al., Identification of a novel SBF2 missense mutation associated with a rare case of thrombocytopenia using whole-exome sequencing. J Thromb Thrombolysis, (4): p Conforti, F.L., et al., A new SBF2 mutation in a family with recessive demyelinating Charcot-Marie-Tooth (CMT4B2). Neurology, (7): p Kirwan, M., et al., Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum t, (5): p Committed to CUSTOMIZED DIAGNOSTICS, TRANSLATIONAL RESEARCH & YOUR PATIENTS NEEDS