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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. SBDS is the only gene currently known to be associated with SDS. Molecular genetic testing is clinically available.
Management. Treatment of manifestations: Care by a multidisciplinary team is recommended. Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation. Blood and/or platelet transfusions may be considered for anemia and bi- or trilineage cytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently 500/mm3 or less, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered. Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe pancytopenia, MDS, or AML. Prevention of secondary complications: aggressive dental hygiene to promote oral health. Consider prophylactic antibiotics and G-CSF to reduce risk of infection during complex dental procedures or orthopedic surgery. Surveillance: assessment of development, growth, and nutritional status every six months. Complete blood counts at least every six months. Following baseline examination, bone marrow examination every one to three years or more frequently if bone marrow changes are observed. Agents/circumstances to avoid: Prolonged use of cytokine and hematopoietic growth factors (such as G-CSF) should be considered with caution. Case reports have indicated that standard preparative regimens for HSCT with cyclophosphamide or cyclophosphamide and busulfan may lead to cardiac toxicity; milder ablation regimens are being considered.
Genetic counseling. SDS is inherited in an autosomal recessive manner. Most parents of children with SBDS mutations are carriers; however, de novo mutations have been reported. When both parents are known to be carriers, the sibs of a proband have a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for relatives at risk and prenatal testing for pregnancies at increased risk are possible if both disease-causing mutations in a family are known.
The clinical diagnosis of Shwachman-Diamond syndrome (SDS) relies on evidence of exocrine pancreatic dysfunction and bone marrow failure with single- or multi-lineage cytopenia [Rothbaum et al 2002].
Exocrine pancreatic dysfunction can be documented with any one of the following:
An abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease) plus abnormal exocrine pancreas on imaging
Low serum concentrations of the digestive enzymes pancreatic isoamylase and cationic trypsinogen
Deficiency in pancreatic enzyme secretion following quantitative pancreatic stimulation testing with intravenous cholecystokinin and secretin
Note: Exocrine pancreatic dysfunction may be difficult to detect because the production of individual pancreatic enzymes varies during childhood and because severe perturbations of enzyme levels are required to meet diagnostic criteria [Schibli et al 2006]:
Serum pancreatic isoamylase concentration is not reliable in children younger than age three years [Ip et al 2002].
Serum cationic trypsinogen concentration increases to pancreatic-sufficient levels during early childhood in approximately 50% of children with SDS [Durie & Rommens 2004].
Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies with ultrasonography or CT reveal small size for age. In a series of persons with mutation-positive SDS, MRI revealed fatty infiltration with retained ductal and islet components [Toiviainen-Salo et al 2008].
Hematologic abnormalities caused by bone marrow dysfunction involve one or more of the following:
Persistent or intermittent depression of at least one myeloid lineage:
Neutropenia (established with an absolute neutrophil count <1,500 neutrophils /mm3 for ≥3 measurements taken over a period of ≥3 months)
Thrombocytopenia (persistent, with platelet count <150,000 platelets/mm3)
Anemia (with hemoglobin concentration below the normal range for age)
Pancytopenia (trilineage cytopenia with persistent neutropenia, thrombocytopenia, and anemia)
Bone marrow examination may reveal the following:
Varying degrees of hypocellularity and fatty infiltration of the marrow compartments, indicating marrow failure and disordered hematopoiesis
Maturation arrest or delay in single- or multiple-myeloid lineages
Aplastic anemia and myelodysplasia with or without abnormal cytogenetic findings. When cytogenetic anomalies are present, they can be monosomy 7, isochromosome 7, or other chromosomal changes seen in bone marrow failure syndromes.
Studies in which patient and non-patient marrow cells are co-cultured indicate problems with both the stem cell and stromal microenvironment compartments [Dror & Freedman 1999]. These findings, together with the wide range of abnormalities seen in the bone marrow, are consistent with SDS being a bone marrow failure syndrome.
Other. Variation in severity and clinical manifestations complicate the ability to establish a definitive diagnosis of SDS. Other primary features used in support of the diagnosis:
Short stature
Skeletal abnormalities
Hepatomegaly with or without elevation of serum aminotransferase levels
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. SBDS is the only gene presently known to be associated with SDS [Boocock et al 2003].
Other loci. A limited number (<10%) of persons with clear clinical indications of SDS do not appear to have mutations in SBDS, suggesting that mutations in another gene(s) may be causative.
Clinical testing
Targeted mutation analysis. In more than 90% of individuals with SDS, at least one of the mutant SBDS alleles has resulted from a phenomenon known as gene conversion (see Molecular Genetics). The three most common gene conversion mutations, accounting for more than 76% of disease alleles:
In more than 62% of affected individuals, the above mutations account for both disease-causing alleles.
Sequence analysis. The common gene conversion mutations can be detected by direct sequencing of exon 2 [Boocock et al 2003], accounting for 76% of the SDS-causing alleles in more than 200 families [Author, unpublished]. Most of the other rare mutations, including splicing mutations, short insertions or deletions, and missense mutations, can be identified by direct sequencing of the five exons of SBDS.
Research testing
Unusual mutations that involve exon deletions [Costa et al 2007], extended conversions of exon 2 and flanking introns, or gene rearrangements involving exon 2 have been observed but may not be detected readily with routine sequencing [Author, unpublished]. In these cases, testing with methods that detect the number of copies of SBDS exons is necessary (e.g., quantitative PCR methods); however, their interpretations must consider the occurrence of the pseudogene. The extent of variation in the pseudogene is not known.
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| SBDS | Targeted mutation analysis | Common mutations c.183_184delinsCT, c.258+2T>C, and c.[183_184delinsCT; 258+2T>C] 1 | 76% 2 | Clinical
 |
| Sequence analysis | Sequence variants, including the common mutations listed above | >90% 3 |
1. Targeted mutations, and therefore detection frequencies, may vary among laboratories.
2. Targeted mutation analysis for these three common mutations can detect at least one mutation in 90% of affected individuals.
Interpretation of test results
To interpret the common gene conversion mutations identified by targeted mutation analysis, parents should be tested to determine whether the mutation(s) observed in their child are:
Monoallelic (e.g., c.[183_184delinsCT; 258+2T>C] on one chromosome and a normal allele on the other chromosome)
OR
Biallelic (e.g., c.183_184delinsCT on one chromosome and c.258+2T>C on the other chromosome)
For issues to consider in interpretation of sequence analysis results, click here.
Confirmation of the diagnosis in a proband. If both exocrine pancreatic dysfunction and characteristic hematologic abnormalities are present, it is appropriate to proceed with molecular genetic testing of SBDS:
Targeted mutation analysis for the three common mutations in exon 2 can detect at least one mutation in 90% of affected individuals.
If no mutation or only one mutation is identified using targeted mutation analysis, sequence analysis of the whole coding region can be performed.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.
No other phenotypes are known to be associated with variations in SBDS.
Note: (1) Although a recent publication suggested that carriers with one normal and one disease-causing SBDS allele may be at higher-than-average risk for aplastic anemia [Calado et al 2007], methodic problems with this study may include the following:
Background risk of being a SBDS carrier (1/139) did not appear to be considered.
Criteria for performing sequence analysis on individuals with aplastic anemia were not clearly delineated.
(2) Aplastic anemia has not been observed in SBDS heterozygotes (i.e., carriers) of more than 200 families with SDS [Authors, personal observation].
(3) Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogeneous leukemia (AML) did not reveal any SBDS mutations [Majeed et al 2005].
The clinical spectrum of Shwachman-Diamond syndrome (SDS) is broad and varies among affected individuals, even sibs [Ginzberg et al 1999]. Despite this variability, both gastrointestinal and hematologic findings are observed in all affected individuals [Cipolli et al 1999, Ginzberg et al 1999].
Neonates generally do not show manifestations of SDS; however, early presentations have included acute life-threatening infections and asphyxiating thoracic dystrophy caused by rib cage restriction. Rare neonatal presentations have also included severe bone marrow failure and aplastic anemia [Kuijpers et al 2005] or severe spondylometaphyseal dysplasia [Nishimura et al 2007].
More commonly, SDS presents in infancy with failure to thrive and poor growth secondary to exocrine pancreatic dysfunction, and recurrent infections secondary to neutropenia and impaired neutrophil chemotaxis, which are likely the most critical contributors to frequent recurrent infections, especially in young children [Dror & Freedman 2002, Stepanovic et al 2004, Kuijpers et al 2005]. Persistent or intermittent neutropenia is recognized first in almost all affected children, often before the diagnosis is made; in one series of 88 children, neutropenia was a presenting finding in 98% [Ginzberg et al 1999]. Acute and deep-tissue infections can be life threatening, particularly in young children [Cipolli 2001, Grinspan & Pikora 2005].
The risk for leukemia, typically AML, may be 15%-25% or higher in individuals with SDS than in the general population [Dror & Freedman 2002]. Although information is limited to a few studies, a retrospective survey over 25 years revealed that seven of 21 individuals with SDS developed myelodysplastic syndrome; five of the seven developed AML [Smith et al 1996]. In a more recent study, eight of 71 persons with SDS developed MDS and/or leukemia over a ten-year period [Donadieu et al 2005].
The risks for transformation with dysplastic cytologic abnormalities and AML are considered to be lifelong; AML is generally associated with poor outcome [Donadieu et al 2005]. The risk for malignancies other than AML does not appear to be increased, but information to date is limited.
Characteristic skeletal changes appear to be present in all mutation-positive individuals [Mäkitie et al 2004]; however, skeletal manifestations vary among individuals and over time. In some individuals the skeletal findings may be sub-clinical.
Cross-sectional and longitudinal data from the study of Mäkitie et al [2004] revealed the following:
Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed
Variable widening and irregularity of the metaphyses in early childhood (i.e., metaphyseal chondrodysplasia), followed by progressive thickening and irregularity of the growth plates
Generalized osteopenia
Of note, the epiphyseal maturation defects tended to normalize with age and the metaphyseal changes tended to progress (worsen) with age [Mäkitie et al 2004].
Additional skeletal findings can include rib abnormalities and joint abnormalities, the latter of which can result from asymmetric growth and can be sufficiently severe to warrant surgical intervention.
Children with adequate nutrition and pancreatic enzyme supplementation have normal growth velocity and appropriate weight for height; however, approximately 50% of children with SDS are below the third percentile for height and weight [Durie & Rommens 2004].
Hepatomegaly and liver dysfunction with elevated serum aminotransferase concentration can be observed in young children, but tend to resolve by age five years. Mild histologic changes may also be evident in biopsies, and although they do not appear to be progressive, it has been noted that liver complications have occurred in older individuals following bone marrow transplantation [Ritchie et al 2002].
Other possible findings:
Ichthyosis and eczematous lesions
Oral disease including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [Ho et al 2007]
Cognitive and/or behavioral problems [Cipolli et al 1999, Ginzberg et al 1999]; however, few studies have described their full extent and range [Kent et al 1990; E Kerr, personal communication].
Immune dysfunction [Dror et al 2001]
Kidney or urinary tract anomalies
No genotype-phenotype correlations have been observed with SBDS mutations [Mäkitie et al 2004; Kawakami et al 2005; Kuijpers et al 2005; Author, unpublished]; this is consistent with the earlier observed phenotypic variability among affected sibs [Ginzberg et al 1999].
SDS has previously been known as:
Shwachman’s syndrome
Congenital lipomatosis of the pancreas
Shwachman-Bodian syndrome
It has been estimated that SDS occurs in one of 76,000 births based on the observation that it is approximately 1/20th as frequent as cystic fibrosis in North America [Goobie et al 2001].
SDS occurs in diverse populations including those with European, Indian, aboriginal (North America), Chinese, Japanese, and African ancestry.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Features of Shwachman-Diamond syndrome (SDS) in early childhood, such as poor growth and transient neutropenia, may have multiple causes in young children.
Pancreatic dysfunction
Cystic fibrosis, which often presents with both upper-respiratory infections and exocrine pancreatic dysfunction, can be distinguished from SDS by sweat chloride testing and absence of primary bone marrow failure.
Other conditions with exocrine pancreatic dysfunction:
Johanson-Blizzard syndrome, which can be distinguished from SDS by the characteristic anomalies, severe developmental delays, and absence of hematologic abnormalities
Pearson bone marrow-pancreas syndrome, a rare mitochondrial disorder with both exocrine pancreatic dysfunction and bone marrow dysfunction, which can be distinguished from SDS by bone marrow examination and molecular genetic testing
Exocrine pancreatic insufficiency can also result from severe malnutrition.
Other bone marrow failure syndromes that overlap in some respects with SDS include the following:
Diamond-Blackfan anemia
Dyskeratosis congenita
These conditions and aplastic anemia can often be excluded by clinical investigations and bone marrow examination. Primary exocrine pancreatic dysfunction is not known to occur is these related syndromes.
Neutropenia
Transient neutropenia can result from medications or infections.
Clinical findings, repeated assessments of hematologic findings, and molecular genetic testing reliably distinguish SDS from Kostmann congenital neutropenia and ELA2-related neutropenia.
Skeletal dysplasia
Cartilage-hair hypoplasia (CHH) syndrome has gastrointestinal, skeletal, hematologic, and immunologic features. However, the skeletal anomalies of CHH can be distinguished from those of SDS, and the gastrointestinal features of CHH are secondary to complications of infections rather than to exocrine pancreatic insufficiency.
To establish the extent of disease following the initial diagnosis of Shwachman-Diamond syndrome (SDS), the following evaluations to assess the status of the pancreas, liver, bone marrow, and skeleton are recommended:
Assessment of growth: height, weight in relation to age
Assessment of developmental milestones (including pubertal development)
Assessment of nutritional status to determine if supplementation with pancreatic enzymes is necessary and/or effective:
Measurement of fat-soluble vitamins (vitamin A, 25-OH-vitamin D, and vitamin E) or their related metabolites
Measurement of prothrombin time (to detect vitamin K deficiency)
Assessment of serum concentration of the digestive enzyme cationic trypsinogen and, if sufficiency is observed, followed by confirmation with 72-hour fecal fat balance study (with discontinuation of enzyme supplementation for at least a 24-hour period)
Assessment of serum aminotransferase levels
Complete blood count with white cell differential and platelet count at six-month intervals (or more often as clinically indicated)
Bone marrow examination with biopsy and cytogenetic studies at initial assessment (Note: Current practice typically involves these studies; discussions to develop uniform recommendations are ongoing.)
Skeletal survey with radiographs of at least the hips and lower limbs
A multidisciplinary team that includes specialists from the following fields is recommended: hematology, gastroenterology, medical genetics, orthopedics, endocrinology, immunology, dentistry, child development, psychology, and social work as needed [Dror & Freedman 2002, Rothbaum et al 2002, Durie & Rommens 2004].
Exocrine pancreatic insufficiency can be treated with the same oral pancreatic enzymes commonly used in treatment of cystic fibrosis; dose should be based on results of routine assessment of pancreatic function and nutritional status. Steatorrhea often resolves in early childhood, but pancreatic enzyme levels can remain low; routine monitoring (see Surveillance) is recommended.
Supplementation with fat-soluble vitamins (A, D, E, and K) is recommended.
Blood and/or platelet transfusions may be considered for anemia and bi- or trilineage cytopenia.
If recurrent infections are severe and absolute neutrophil counts are persistently 500/mm3 or less, treatment with prophylactic antibiotics and granulocyte-colony stimulation factor (G-CSF) can be considered.
Hematopoietic stem cell transplantation (HSCT) can be considered for treatment of severe pancytopenia, bone marrow transformation to myelodysplastic syndrome, or AML. Cells from both bone marrow and cord blood have been used. Although earlier reports indicate that survival is fair, cautious myeloablation and newer regimens show promise for improving outcomes [Cesaro et al 2005; Vibhakar et al 2005; Sauer et al 2007; R Harris, personal communication].
Note: Bone marrow abnormalities, per se, are not treated unless severe aplasia, myelodysplastic fluxes, or leukemic transformation are present.
Children with poor growth and delayed puberty benefit from ongoing consultation with an endocrinologist, who may also consult with orthopedists regarding possible surgical management of asymmetric growth and joint deformities.
Although cognitive, learning, and behavioral features of SDS have been less well investigated than other aspects, remedial interventions are considered beneficial [E Kerr, personal communication].
For pregnancies in women with SDS, high-risk pregnancy care including consultation with a hematologist is recommended.
Frequent dental visits to monitor tooth development and oral health are recommended to reduce the incidence of mouth ulcers and gingivitis. Home care should include aggressive dental hygiene with topical fluoride treatments to help prevent dental decay [M Glogauer, personal communication].
Prophylactic antibiotics and G-CSF may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered.
The following is recommended given the intermittent nature of some features of SDS and the evolution of the phenotype over time [Rothbaum et al 2002]:
Developmental and growth assessment every six months
Assessment of nutritional status every six months and measurement of serum concentration of vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
Complete blood counts with white blood cell differential and platelet counts at least every six months, or more frequently if infections are recurrent and debilitating
Current practice is to repeat bone marrow examinations every one to three years following the baseline examination. These should be more frequent if changes in bone marrow function or cellularity are observed.
Note: Discussions to develop uniform recommendations are ongoing.
Monitoring for orthopedic complications resulting from growth during childhood with bone density measurements and x-rays of hips and knees during the most rapid growth stages
Prolonged use of cytokine and hematopoietic growth factors such as G-CSF is cautioned against in view of the potential for contribution to leukemic transformation [Rosenberg et al 2006].
Some drugs, such as cyclophosphamide or cyclophosphamide and busulfan, typically used in standard preconditioning or preparative regimens for bone marrow transplantation may not be suitable because of possible cardiac toxicity [Mitsui et al 2004, Cesaro et al 2005, Vibhakar et al 2005, Sauer et al 2007].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Shwachman-Diamond syndrome (SDS) is inherited in an autosomal recessive manner. The mode of inheritance of SDS in individuals without identified SBDS mutations is unknown.
Parents of a proband
The parents of an affected child are usually heterozygotes (i.e., carriers of one mutant allele).
Occasionally, only one parent is a carrier as the affected child has one inherited and one de novo SBDS allele.
Heterozygotes are asymptomatic. See Genetically Related Disorders.
Sibs of a proband
When both parents are known to be carriers
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
When the proband has one inherited and one de novo mutation. At conception, each sib of an affected individual has a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic. See Genetically Related Disorders.
Offspring of a proband. The offspring of an individual with SDS are obligate heterozygotes (carriers) for a disease-causing mutation. In the rare event that the reproductive partner of the proband is a carrier, the offspring are at a 50% risk of being affected and a 50% risk of being carriers.
Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is possible once the mutations have been identified in the family.
Family planning
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| SBDS | 7q11 | Ribosome maturation protein SBDS | SBDSbase: Mutation registry for Shwachman-Diamond syndrome | SBDS |
Normal allelic variants: The SBDS locus involves a total of five exons and spans less than 9 kb. Notable aspects of the gene are its pericentromeric location on chromosome 7q and occurrence within a 305-kb segment that appears duplicated and inverted, 5.8 megabases (Mb) distally [Boocock et al 2003]. Some of the normal allelic variants reflect the sequence of the pseudogene (SBDSP), indicating that they may have arisen by gene conversion events between the gene and the pseudogene.
Pathologic allelic variants: The abnormalities identified in individuals with SDS lead to prematurely truncated proteins, splicing aberrations, and missense alterations.
At least one allele in >90% of individuals with Shwachman-Diamond syndrome (SDS) has a mutation that apparently arose by gene conversion. The gene conversion event occurred between the functional SBDS gene and a nonfunctional pseudogene copy (SBDSP), which has 97% sequence identity to SBDS. The high sequence identity between these two genes facilitates gene conversion, a phenomenon whereby a small segment of SBDS is replaced by a segment copied from the SBDSP pseudogene. Therefore, this segment of SBDS has sequence variants typical of the pseudogene; the variants that inactivate normal SBDS gene expression and/or translation of normal protein are pathogenic.
The three most common converted pathologic alleles:
c.183_184delinsCT
c.258+2T>C
c.[183_184delinsCT; 258+2T>C].
Note: This allele has a longer converted segment with both variants occurring on one allele.
These three alleles account for more than 76% of disease-causing alleles.
Other alleles with more extensive converted regions involving exon 2, neighboring introns, and exon 1 have also been found [Authors, unpublished]. The rare c.297_300delAAGA mutation is also likely the consequence of gene conversion with SBDSP but involves only the exon 3 region.
Except for one reported case to date, affected individuals with rare mutations occur as compound heterozygotes with one of the three common gene conversion mutations. In the one exception, an individual with a clinical diagnosis of SDS had two rare missense alleles in exons 3 and 4, respectively [Erdos et al 2006].
| Class of Variant Allele | DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Normal | c.141C>T 2 | p.(=) 4 | NM_016038.2 NP_057122.2 |
| c.201A>G 2 | p.(=) | ||
| c.635T>C 3 | p.Ile212Thr | ||
| c.651C>T | p.(=) | ||
| Pathologic | c.119delG | p.Ser41AlafsX18 | |
| c.183_184delinsCT 2 (c.183TA>CT) | p.Lys62X | ||
| c.[183_184delinsCT; 258+2T>C] 2 | p.Lys62X | ||
| c.258+1G>C | -- | ||
| c.258+2T>C 2 | p.Cys84TyrfsX4 | ||
| c.297_300delAAGA 2 | p.Glu9AspfsX20 | ||
| c.377G>C | p.Arg126Thr | ||
| c.505C>T | p.Arg169Cys | ||
| c.624+1G>C | -- | ||
| c.652C>T | p.Arg218X |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
2. Likely the consequence of gene conversion with SBDSP
3. Initially reported to be a possible pathogenic allele
4. The designation p.(=) means that the protein has not been analyzed, but no change is expected.
Normal gene product: SBDS encodes a highly conserved protein of 250 amino acids that appears to occur in all animals, plants, and archea [Boocock et al 2003]. The structural analysis of an archeal ortholog indicates that the SBDS protein contains three domains [Savchenko et al 2005, Shammas et al 2005].
The modeling of several of the identified missense mutations onto the three-domain structure of the solved archael SBDS protein ortholog supports the likelihood that they are pathogenic [Savchenko et al 2005, Shammas et al 2005]. The SBDS protein is thought to play a role in RNA metabolism and ribosome biogenesis, and more recent genetic studies of the yeast homolog support a role in 60S ribosomal subunit biogenesis and translational activation [Menne et al 2007].
Abnormal gene product: The mutations identified in individuals with SDS led to prematurely truncated proteins, splicing aberrations, and missense alterations. These mutations are predicted to result in absence or loss of function of the SBDS protein. Despite the relatively common occurrence of the null allele c.183_184delinsCT (p.Lys62X), no homozygotes have been reported. This is consistent with the observations of a mouse model in which complete loss of both Sbds alleles was not compatible with life [Zhang et al 2006]. It is therefore anticipated that some residual activity of the SBDS protein is required for development to occur.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
We thank individuals with Shwachman-Diamond syndrome, and their families and care givers for their cooperation.
17 July 2008 (me) Review posted live
7 January 2008 (jr) Original submission
