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Version 1. PLoS Curr. 2012 May 2; 4: e4f9877ab8ffa9.
PMCID: PMC3392137
Evidence on Genomic Tests

Comprehensive Carrier Screening and Molecular Diagnostic Testing for Recessive Childhood Diseases

Stephen Kingsmore, MB ChB BAO DSc FRCPath*


Of 7,028 disorders with suspected Mendelian inheritance, 1,139 are recessive and have an established molecular basis. Although individually uncommon, Mendelian diseases collectively account for ~20% of infant mortality and ~18% of pediatric hospitalizations. Molecular diagnostic testing is currently available for only ~300 recessive disorders. Preconception screening, together with genetic counseling of carriers, has resulted in remarkable declines in the incidence of several severe recessive diseases including Tay-Sachs disease and cystic fibrosis. However, extension of preconception screening and molecular diagnostic testing to most recessive disease genes has hitherto been impractical. Recently, we reported a preconception carrier screen / molecular diagnostic test for 448 recessive childhood diseases. The current status of this test is reviewed here. Currently, this reports analytical validity of the comprehensive carrier test. As the clinical validity and clinical utility in the contexts described is ascertained, this article will be updated.

Clinical Scenarios

The test is designed both for preconception carrier testing of couples wishing to start a family and for molecular diagnosis in children suspected of being affected by a recessive childhood disease. The published (research) version of the test included 448 childhood recessive illnesses with severe clinical manifestations1. A revised panel is undergoing clinical validation for use as a laboratory developed test (LDT) with an intention of being offered via a laboratory regulated by the Clinical Laboratory Improvement Amendments (CLIA). The clinical panel contains 595 childhood recessive diseases that are deemed to meet American College of Medical Genetics (ACMG) criteria for implementation of genetic testing for ultra-rare disorders2. Validation of analytic utility is being performed for the clinical scenarios detailed below prior to test offering. Initial validation of clinical utility and cost effectiveness will occur over the next year.

1. Preconception carrier testing for recessively inherited diseases of childhood.

Prepregnancy carrier testing is currently offered to couples desiring to start a family in order to provide individualized genetic counseling about risk of conceiving a child affected by a specific recessively inherited diseas3 4. The test performs preconception carrier testing for 595 recessive diseases simultaneously and three target populations are envisaged:

i. Couples undergoing in vitro fertilization (IVF) procedures. Testing of couples, pretesting of sperm and egg donors and genetic counseling is of utility for reduction in risk of having an affected child. Given the economics of IVF, the incremental cost of carrier testing is unlikely to be a barrier to adoption5. Screening of sperm and oocyte donors has lower counseling burden than other clinical scenarios6. Further, the motivation of couples undergoing IVF procedures is anticipated to facilitate adoption. Since testing is performed before conception, some of the ethical concerns of carrier testing in other clinical scenarios are not relevant3 6. We are not aware of published studies of efficacy in this target population. It should be noted that knowledge of mutations in many of the 595 diseases is incomplete and testing is anticipated to reduce but not eliminate the risk of an affected child.

ii. Individuals and populations at high risk of recessive disorders. Examples include populations with genetic bottlenecks and / or higher rates of consanguinity. Ashkenazi Jewish populations, Arab populations, Amish populations and individuals with a family history of recessive diseases are examples. Preconception testing of motivated populations for recessive disease mutations, together with education and genetic counseling of carriers, can dramatically reduce disease incidence in a generation. The broad rationale is the success of testing north American Ashkenazi Jewish populations for carrier status of Tay-Sachs disease (TSD; Mendelian Inheritance in Man accession number OMIM# 272800)7 8 9 10 11 12 13.

iii. General population testing. Given a recent report that we each harbor an average of 2.8 known recessive severe childhood disease mutations1, there is theoretical utility of voluntary carrier testing in general populations14. The broad rationale is the success of general population testing for carrier status of cystic fibrosis [CF, OMIM#219700]12 13 15 16 17 18 19. Practical clinical utility requires a). the cost to be low, b). provision of pre- and post-test genetic counseling (including delineation of the potential benefits and harms of carrier test results) and, c). protections for confidentiality, privacy and against stigmatization or discrimination. The ideal age for recessive disease screening is in early adulthood and before pregnancy. In the US, preconception carrier testing is hospital-based, whereas community-based testing has had success in Canada and Australia9 19 20 21 22. Community-based population testing has advantages over testing in a hospital setting, where information about carrier testing often is communicated during pregnancy or after the birth of an affected child9 19 20 21 22. Community-based carrier testing has had high uptake, without apparent stigma or discrimination and with substantial reductions in the frequencies of tested disorders9 19 20 21 22. Of note, the United Kingdom's Human Genetics Commission recently reported that it found no specific social, ethical or legal principles that would make preconception genetic testing within the framework of a population screening program unacceptable14.

Preconception carrier testing for 595 diseases is anticipated to be offered initially as an LDT in late 2011 in the first two clinical scenarios. Expansion to general population testing is anticipated subsequently upon demonstration of cost effectiveness and validation of clinical utility in targeted populations. Revision of national policies for carrier testing is anticipated to be needed in response to next-generation-sequencing based multiplexed tests such as this.

2. Diagnostic testing in potentially affected children.

Diagnostic carrier testing is offered to affected children (via parents) suspected of having a recessively inherited disease in order to determine a definitive diagnosis and, thereby, individualize treatment and genetic counseling2. The broad rationale is that the test is an extension of conventional, univariate, serial molecular genetic testing. However, conventional approaches have severe limitations: Hundreds of recessive illnesses exist for which conventional molecular diagnosis is technically feasible but not available. They are too uncommon for commercially-viable conventional genetic testing or blocking patents exist. As a result, knowledge of mutation spectrum, genotype-phenotype relationships and allele frequencies in diseases without molecular diagnosis are rudimentary, inhibiting development of investigational new drugs. Of those for which molecular tests are available, many present as progressive multisystem disorders, requiring lengthy and costly differential diagnosis in a conventional genetic testing scenario, exhausting resources of patients, families and physicians. Thus, typically, <50% of patients undergoing conventional genetic testing receive a molecular diagnosis despite average testing cost per patient of >$10,000. Furthermore, serial univariate testing can take over a year, delaying timely intervention or counseling. It should be noted that our knowledge of mutations in many of the 595 diseases is incomplete and thus testing will not provide definitive diagnosis in all affected children. The scope of diagnostic use of the test is in differential diagnosis of affected children suspected of having one of the 595 diseases. The intended test use is in molecular diagnosis.

Test Description

The test is as described1, but has been modified for clinical testing as follows: Genomic DNA is prepared from patient EDTA-blood samples. 2.6 million nucleotides of target genomic regions, representing exons, intron boundaries and non-exonic mutation containing regions in 527 genes are enriched ~500-fold from the 3.16 billion nucleotide (nt) genome of each sample. Enrichment uses hybrid capture, in which tens of thousands of oligonucleotide probes capture 8,614 genomic DNA fragments, collectively comprising 592 disease genes. Patient DNA is fragmented, denatured and incubated with the oligonucleotides. The target-oligonucleotide hybrids are isolated by magnetic capture23. Next generation sequencing of the enriched targets is performed with Illumina HiSeq and TruSeq sequencing-by-synthesis, yielding ~3 billion nucleotides of sequence per sample, each ~125 nucleotides long. Sequences are aligned to the reference human genome uniquely, covering each target nucleotide ~150 times. Alignment uses the algorithm GSNAP24 25, with parameters that have been optimized for clinical diagnostic use. Enrichment and sequencing are performed on multiplexed samples, which are disambiguated by molecular barcodes. ~1% of target nucleotides are not covered, while ~95% of target nucleotides have at least 16-fold sequence coverage. The majority of missed nucleotides are in high GC-content targets, are missed reproducibly, and are labelled as such. An automated bioinformatic decision tree is used to identify and genotype variations in the aligned sequences24 26 27 28 29 30. Variants are retained if present in at least 8 sequences of quality score >25 and in exons with at least 16-fold sequence coverage24. Variants detected in >86% of reads are considered homozygous, while those present in 14-86% of reads are heterozygous. Variants are classified according to ACMG and other guidelines2 18 31 32 33 34 35, using literature knowledge as well as in silicotools, such as comparison with a variety of mutation and human variation databases, PolyPhen-2 and SIFT, to determine the pathogenicity of each variant. Pathogenic variants are assembled into genotypes and reported. For diagnostic testing, where variants are of uncertain significance, further evidence is sought, using additional in silico tools, literature evidence, clinico-pathologic correlation, confirmatory family studies or functional assays, as appropriate. In general, variant interpretation is identical to that performed using conventional molecular diagnostic assays with the exceptions that clinico-pathologic interpretation and masking of non-relevant genes are routine in diagnostic use of the assay and that ~90% of variant annotation and reporting is automated, facilitating interpretation and standardization of reporting. Reporting of variants differs in carrier testing of adults and diagnostic testing of children31. Carrier testing reports carrier status in all genes. Diagnostic testing reports positive and negative results in genes relevant to the clinical presentation. Diagnostic testing in children does not report carrier status in genes that are not relevant to presentation31. In a subset of cases, further communication between the laboratory director and ordering physician is necessary to guide additional studies and assist in interpretation.

Public Health Importance

Mendelian diseases collectively affect 13 million people in the US, accounting for ~20% of infant mortality and ~18% of pediatric hospitalizations36 37 38 39 40.

Diagnostic testing in potentially affected children

Simultaneous diagnostic testing for 595 recessive childhood diseases is anticipated to have several public health impacts: 1). Extension of the prevention, diagnosis, and treatment benefits demonstrated for conventional genetic testing to hundreds of recessive diseases for which testing is not available today; 2). Reduction in time-to-diagnosis, particularly in illnesses where the differential diagnosis is broad and the conventional approach is serial univariate testing. Serial univariate testing can take over a year, delaying timely intervention or counseling. The initial turnaround time of the test will be 4 weeks. 3). Reduction in cost of diagnosis. The average cost per patient of serial univariate molecular diagnostic testing is ~$10,000 at our institution. The test is anticipated to cost ~$600. 4). Increased rate of definitive molecular diagnosis. Less than 50% of patients undergoing serial univariate molecular diagnostic testing receive a molecular diagnosis. This is anticipated to increase with test use, particularly in illnesses where the differential diagnosis is broad, such as mitochondrial myopathies or intellectual disability. Timely diagnosis of affected individuals has several potential benefits:

1. Prevention of death or markedly diminished disease severity where curative treatments are available. Quite a large number of recessive diseases have specific therapies. Neonatal diagnosis and treatment of phenylketonuria (PKU) and congenital hypothyroidism prevent severe intellectual disability. Likewise, death is prevented in certain forms of congenital adrenal hyperplasia (CAH), medium chain acyl-coA dehydrogenase deficiency (MCAD), and galactosemia (OMIM #230400).

2. Genetic counseling of patients and families about risks for relatives and in additional offspring.

3. Improvement in quality of life in disorders where treatments are ameliorative. While many recessive diseases lack curative treatments, timely diagnosis nevertheless allows specific interventions that can substantially improve quality of life. Such interventions may slow disease progression, lessen symptoms, prevent complications or improve function in affected organ systems.

4. Substantial psychosocial benefits with respect to anxiety, self-image, uncertainty and lifestyle decisions.

5. Multiplexed testing allows rule-out of differential diagnoses, decreasing unnecessary treatments.

Use of the research version of the test revealed that 27% of literature mutations are common polymorphisms or misannotated1. Thus, it is critical to establish a clinical grade mutation database for recessive illnesses. Implementation of the test for diagnosis in affected children will, with time, improve the quality and quantity of annotated mutations, particularly for diseases that for which no molecular test is available currently.

In addition, test results have a cumulative potential to inform an understanding of disease mechanisms. In each individual with a Mendelian disorder, the specific mutations impact the age of onset, disease severity, rates of progression, distribution of affected organs, complications, pleiotropy and outcomes. Only in diseases for which molecular diagnosis is undertaken can such knowledge be accumulated. A broad understanding of genotype-phenotype relationships can enable individualized care of patients with recessive diseases. This can potentially include individualized treatment intensity and prediction of disease progression, severity and likely complications. Thus, in the long term, the test, when performed in a research setting, can allow identification of genotype-phenotype relationships that allow conveyance of individualized diagnostic information.

Initial experience with the test has revealed the existence of novel modifier mutations and pleiotropy in patients with recessive illnesses (Kingsmore et al., submitted). Only through multiplexed molecular testing can such knowledge be accumulated. A broad understanding of modifier genes can further enable individualized care of patients with recessive diseases. Thus, in the long term, the test, when performed in a research setting, can allow identification of modifier genes that allow conveyance of individualized diagnostic information.

Finally, timely molecular diagnosis can allow intervention before organ decompensation, when treatment is likely to alter outcomes. Currently, study of new therapies for rare disorders are hampered by diagnosis after organ damage and low rates of ascertainment. Timely diagnosis can permit regional referral of affected individuals for specialized treatment.

It should be noted that substantiation of the potential public health impacts in prevention, diagnosis, or treatment of recessive childhood illnesses is needed. Such assessments should include measurement of cost effectiveness including costs of follow up of ambiguous test results and counseling.

Published Reviews, Recommendations and Guidelines

Systematic evidence reviews

The emerging use of targeted sequencing of panels of genes, whole exome sequencing and whole genome sequencing for molecular diagnosis of Mendelian diseases was recently reviewed45.

Recommendations by independent group

Currently none.

Guidelines by professional groups

The United Kingdom's Human Genetics Commission recently reported guidance on preconception genetic testing within the framework of a population screening program14.

Evidence Overview

Analytic Validity:

The 437 genes responsible for 448 childhood recessive diseases are listed in Table 1. Using genotyping cut-offs of 14% and 86% to differentiate homozygotes and heterozygotes and >20X nucleotide coverage and >10 reads of quality >20 to call a variant, the accuracy of the test for SNP genotyping was 98.8%, analytic sensitivity was 94.9% and analytic specificity was 99.99% for 92,106 SNPs in 26 samples genotyped both by high density arrays and the test1. The positive predictive value (PPV) of the test for SNP genotyping was 99.96% and negative predictive value was 98.5%, as ascertained by array hybridization1. As sequence depth increased from 0.7 to 2.7GB, test sensitivity increased from 93.9% to 95.6%, whereas PPV remained ~100%. Area under the curve (AUC) of the receiver operating characteristic (ROC) of the test for 92,106 SNP genotypes in 26 samples, when compared with array hybridization, was 0.99 when the number and % reads calling a SNP was varied.

For known substitution, indel, splicing, gross deletion and regulatory alleles in 76 samples, analytic sensitivity was 100% (113 of 113 known alleles). The higher sensitivity for detection of known mutations reflected manual curation. The twenty known indels were confirmed by PCR and Sanger sequencing. Of note, substitutions, indels, splicing mutations and gross deletions account for the vast majority (96%) of annotated mutations27.

Unexpectedly, 14 of 113 literature-annotated disease mutations were either incorrect or incomplete. PCR and Sanger sequencing confirmed that the 14 variants and genotypes called by the test were correct1.

Gross deletions were detected both by perfect alignment to mutant junction reference sequences and by local decreases in normalized coverage (normalized to total sequence generated). Eleven of eleven gross deletion mutations for which boundaries had been defined were identified1. Further analytic validation of ability to detect and genotype gross deletions, gross insertions and complex rearrangements is required.

It should be noted that the clinical version of the test will feature several improvements that are anticipated to improve analytic sensitivity and specificity. These are: 1). Increased depth of sequencing to 3 GB per sample; 2). Automation of the sequencing library preparation and target enrichment; 3). Re-design of the target enrichment oligonucleotides; 4). Change in the variant detection parameters to >16X nucleotide coverage and >6 reads of quality >25 to call a variant; 5). Further refinement of alignment parameters to prevent variant detection solely at the ends of reads; 6). Increased library size to reduce overlap redundancy; 7). Improved sequencing-by-synthesis chemistry (TruSeq); 8). Improved HiSeq instrument specification. Repetition of analytic validation is ongoing in a CLIA-compliant laboratory setting.

Clinical Validity

There are no published systematic evidence reviews of test accuracy, reliability or predictive value in a clinical setting. Experience is being garnered with the use of whole exome or whole genome sequencing for molecular diagnosis of Mendelian diseases and was recently reviewed.

Clinical Utility

There are no published systematic evidence reviews or published clinical trials. Published experience was in a research setting and was not blinded to sample diagnosis1. Test development and assessment of analytic and clinical validity and utility are ongoing.


Last updated: March 18, 2011

Table 1

Table thumbnail

Competing Interests

The author has received in-kind funding from private companies (Illumina Inc., Life Technologies Inc., Roche-Nimblegen and British Airways PLC).


We thank Dr. M. Chandler and Dr. M. Spain, who envisioned universal preconception screening, and the many physicians and geneticists who refined the concept and candidate disease list, particularly Prof. Dr. H.H. Ropers. This test is dedicated to Christiane. A deo lumen, ab amicis auxilium.



Stephen F. Kingsmore joined Children's Mercy Hospital and Clinics, Kansas City, MO, in 2011 to set up pediatric genomic medicine (a structured approach to disease diagnosis & management that prominently features genome sequence information). Previously, Dr. Kingsmore was President of the National Center for Genome Resources, Santa Fe, NM, Chief Operating Officer of Molecular Staging Inc., Vice President of Research of CuraGen Corp. and Assistant Professor at the Univ. Florida. Dr. Kingsmore received a B.Sc., M.B., Ch.B., B.A.O. and D.Sc. from Queen's University Belfast, N. Ireland. He completed residency in Internal Medicine and fellowship in Rheumatology at Duke. He is a Fellow of the Royal College of Pathologists (UK). He has published over one hundred research papers and identified seven disease genes.

Funding Statement

This work was funded by grants from the Children's Mercy Hospital, Beyond Batten Disease Foundation and NIH (RR016480 to F.D.S.), and by in-kind support from Illumina Inc., Life Technologies and British Airways PLC.


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