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. 2012 May 2;4:e4f9877ab8ffa9. [Version 1] doi: 10.1371/4f9877ab8ffa9

Comprehensive Carrier Screening and Molecular Diagnostic Testing for Recessive Childhood Diseases

Stephen Kingsmore
PMCID: PMC3392137  PMID: 22872815

Abstract

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.

Links

http://www.beyondbatten.org/

http://www.ncgr.org/preventing-rare-genetic-diseases

http://hematite.ncgr.org/

www.sciencemag.org/content/331/6014/130.full

http://www.npr.org/2011/01/13/132908098/new-gene-test-screens-nearly-500-childhood-diseases

Last updated: March 18, 2011

Table 1

OMIM# NAME GENE
102700 SEVERE COMBINED IMMUNODEFICIENCY, AR, T CELL-NEGATIVE, ADA
102770 MYOADENYLATE DEAMINASE DEFICIENCY, MYOPATHY DUE TO AMPD1
105830 ANGELMAN SYNDROME AS MECP2
107400 PROTEASE INHIBITOR 1; PI SERPINA1
124000 MITOCHONDRIAL COMPLEX III DEFICIENCY BCS1L
124000 MITOCHONDRIAL COMPLEX III DEFICIENCY UQCRB
124000 MITOCHONDRIAL COMPLEX III DEFICIENCY UQCRQ
133540 COCKAYNE SYNDROME, B; CSB ERCC6
141800 HEMOGLOBIN--ALPHA LOCUS 1; HBA1 HBA1
141900 HEMOGLOBIN--BETA LOCUS; HBB HBB
145900 HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS. CMT3, CMT4F EGR2
145900 HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS. CMT3, CMT4F MPZ
145900 HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS. CMT3, CMT4F PMP22
145900 HYPERTROPHIC NEUROPATHY OF DEJERINE-SOTTAS. CMT3, CMT4F PRX
188055 THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE F5
190685 DOWN SYNDROME GATA1
200100 ABETALIPOPROTEINEMIA; ABL MTTP
200990 ACROCALLOSAL SYNDROME; ACLS GLI3
201000 CARPENTER SYNDROME RAB23
201450 ACYL-CoA DEHYDROGENASE, MEDIUM-CHAIN, DEFICIENCY OF ACADM
201460 ACYL-CoA DEHYDROGENASE, LONG-CHAIN, DEFICIENCY OF ACADL
201470 ACYL-CoA DEHYDROGENASE, SHORT-CHAIN, DEFICIENCY OF ACADS
201475 ACYL-CoA DEHYDROGENASE, VERY LONG-CHAIN, DEFICIENCY OF ACADVL
201710 LIPOID CONGENITAL ADRENAL HYPERPLASIA CYP11A1
201710 LIPOID CONGENITAL ADRENAL HYPERPLASIA STAR
201910 CONGENITAL ADRENAL HYPERPLASIA, 21-HYDROXYLASE DEFICIENCY CYP21A2
202400 AFIBRINOGENEMIA, CONGENITAL FGA
202400 AFIBRINOGENEMIA, CONGENITAL FGB
202400 AFIBRINOGENEMIA, CONGENITAL FGG
203500 ALKAPTONURIA HGD
203700 ALPERS DIFFUSE CEREBRAL DEGENERATION WITH HEPATIC CIRRHOSIS POLG
203780 ALPORT SYNDROME, AR COL4A3
203780 ALPORT SYNDROME, AR COL4A4
203800 ALSTROM SYNDROME; ALMS ALMS1
204200 CEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 CLN3
204500 CEROID LIPOFUSCINOSIS, NEURONAL, 2; CLN2 TPP1
205100 AMYOTROPHIC LATERAL SCLEROSIS 2, JUVENILE; ALS2 ALS2
206700 ANIRIDIA, CEREBELLAR ATAXIA, AND MENTAL DEFICIENCY PAX6
207410 ANTLEY-BIXLER SYNDROME; ABS FGFR2
207900 ARGININOSUCCINIC ACIDURIA ASL
208000 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY; GACI ENPP1
208085 ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS VPS33B
208150 FETAL AKINESIA DEATION SEQUENCE; FADS RAPSN
208400 ASPARTYLGLUCOSAMINURIA AGA
208540 RENAL-HEPATIC-PANCREATIC DYSPLASIA; RHPD NPHP3
208900 ATAXIA-TELANGIECTASIA; AT ATM
208920 EARLY-ONSET ATAXIA WITH OCULOMOTOR APRAXIA AND HYPOALBUMINEMIA APTX
210210 3-METHYLCROTONYL-CoA CARBOXYLASE 2 DEFICIENCY MCCC2
210600 SECKEL SYNDROME 1 ATR
210900 BLOOM SYNDROME; BLM BLM
211600 CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC 1; PFIC1 ATP8B1
211750 C SYNDROME CD96
212065 CONGENITAL DISORDER OF GLYCOSYLATION, Ia; CDG1A PMM2
212066 CONGENITAL DISORDER OF GLYCOSYLATION, IIa; CDG2A MGAT2
212720 MARTSOLF SYNDROME RAB3GAP2
213700 CEREBROTENDINOUS XANTHOMATOSIS CYP27A1
214150 CEREBROOCULOFACIOSKELETAL SYNDROME 1; COFS1 ERCC6
214450 GRISCELLI SYNDROME, 1; GS1 MYO5A
214500 CHEDIAK-HIGASHI SYNDROME; CHS LYST
214950 BILE ACID SYNTHESIS DEFECT, CONGENITAL, 4 AMACR
215045 CHONDRODYSPLASIA, BLOMSTRAND ; BOCD PTH1R
215100 RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, 1; RCDP1 PEX7
215140 HYDROPS-ECTOPIC CALCIFICATION-MOTH-EATEN SKELETAL DYSPLASIA LBR
215150 OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA; OSMED COL11A2
215150 OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA; OSMED COL2A1
215600 CIRRHOSIS, FAMILIAL KRT18
215600 CIRRHOSIS, FAMILIAL KRT8
215700 CITRULLINEMIA, CLASSIC ASS1
216400 COCKAYNE SYNDROME, A; CSA ERCC8
216550 COHEN SYNDROME; COH1 VPS13B
217090 PLASMINOGEN DEFICIENCY, I PLG
217400 CORNEAL DYSTROPHY AND PERCEPTIVE DEAFNESS SLC4A11
218000 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN SLC12A6
219000 FRASER SYNDROME FRAS1
219000 FRASER SYNDROME FREM2
219100 CUTIS LAXA, AR, I EFEMP2
219100 CUTIS LAXA, AR, I FBLN5
219200 CUTIS LAXA, AR, II ATP6V0A2
219700 CYSTIC FIBROSIS; CF CFTR
219750 CYSTINOSIS, ADULT NONNEPHROPATHIC CTNS
219800 CYSTINOSIS, NEPHROPATHIC; CTNS CTNS
219900 CYSTINOSIS, LATE-ONSET JUVENILE OR ADOLESCENT NEPHROPATHIC CTNS
220111 LEIGH SYNDROME, FRENCH-CANADIAN ; LSFC LRPPRC
220290 DEAFNESS, AR 1A GJB2
220400 JERVELL AND LANGE-NIELSEN SYNDROME 1; JLNS1 KCNQ1
222448 DONNAI-BARROW SYNDROME LRP2
222600 DIASTROPHIC DYSPLASIA SLC26A2
223900 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, III; HSAN3 IKBKAP
224050 CEREBELLAR HYPOPLASIA AND MENTAL RETARDATION VLDLR
224410 DYSSEGMENTAL DYSPLASIA, SILVERMAN-HANDMAKER ; DDSH HSPG2
225320 EHLERS-DANLOS SYNDROME, AR, CARDIAC VALVULAR COL1A2
225410 EHLERS-DANLOS SYNDROME, VII, AR ADAMTS2
225750 AICARDI-GOUTIERES SYNDROME 1; AGS1 TREX1
225753 PONTOCEREBELLAR HYPOPLASIA 4; PCH4 TSEN54
226600 EPIDERMOLYSIS BULLOSA DYSTROPHICA, AR; RDEB COL7A1
226650 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ COL17A1
226650 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ ITGB4
226650 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ LAMA3
226650 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ LAMB3
226650 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, NON-HERLITZ LAMC2
226670 EPIDERMOLYSIS BULLOSA SIMPLEX WITH MUSCULAR DYSTROPHY PLEC1
226700 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, HERLITZ LAMA3
226700 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, HERLITZ LAMB3
226700 EPIDERMOLYSIS BULLOSA, JUNCTIONAL, HERLITZ LAMC2
226730 EPIDERMOLYSIS BULLOSA JUNCTIONALIS WITH PYLORIC ATRESIA ITGA6
226730 EPIDERMOLYSIS BULLOSA JUNCTIONALIS WITH PYLORIC ATRESIA ITGB4
226980 EPIPHYSEAL DYSPLASIA, MULTIPLE, WITH EARLY-ONSET DIABETES MELLITUS EIF2AK3
228600 FIBROMATOSIS, JUVENILE HYALINE ANTXR2
228930 FIBULAR APLASIA OR HYPOPLASIA WNT7A
229200 BRITTLE CORNEA SYNDROME; BCS ZNF469
229600 FRUCTOSE INTOLERANCE, HEREDITARY ALDOB
230000 FUCOSIDOSIS FUCA1
230400 GALACTOSEMIA GALT
230500 GM1-GANGLIOSIDOSIS, I GLB1
230600 GM1-GANGLIOSIDOSIS, II GLB1
230800 GAUCHER DISEASE, I GBA
230900 GAUCHER DISEASE, II GBA
231000 GAUCHER DISEASE, III GBA
231050 GELEOPHYSIC DYSPLASIA ADAMTSL2
231530 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY HADH
231550 ACHALASIA-ADDISONIANISM-ALACRIMA SYNDROME; AAA AAAS
231670 GLUTARIC ACIDEMIA I GCDH
231680 MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD ETFA
231680 MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD ETFB
231680 MULTIPLE ACYL-CoA DEHYDROGENASE DEFICIENCY; MADD ETFDH
232200 GLYCOGEN STORAGE DISEASE I G6PC3
232220 GLYCOGEN STORAGE DISEASE Ib SLC37A4
232240 GLYCOGEN STORAGE DISEASE Ic SLC37A4
232300 GLYCOGEN STORAGE DISEASE II GAA
232400 GLYCOGEN STORAGE DISEASE III AGL
232500 GLYCOGEN STORAGE DISEASE IV GBE1
235200 HEMOCHROMATOSIS; HFE HFE
235200 HEMOCHROMATOSIS; HFE HFE2
235550 HEPATIC VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY; VODI SP110
236200 HOMOCYSTINURIA CBS
236250 HOMOCYSTINURIA DUE TO DEFICIENCY OF METHYLENETETRAHYDROFOLATE MTHFR
236490 HYALINOSIS, INFANTILE SYSTEMIC ANTXR2
236670 WALKER-WARBURG SYNDROME; WWS POMT1
236670 WALKER-WARBURG SYNDROME; WWS POMT2
236680 HYDROLETHALUS SYNDROME 1 HYLS1
237300 CARBAMOYL PHOSPHATE SYNTHETASE I DEFICIENCY, HYPERAMMONEMIA CPS1
237310 N-ACETYLGLUTAMATE SYNTHASE DEFICIENCY NAGS
238970 HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME SLC25A15
239000 PAGET DISEASE, JUVENILE TNFRSF11B
240300 AUTOIMMUNE POLYENDOCRINE SYNDROME, I; APS1 AIRE
241200 BARTTER SYNDROME, ANTENATAL, 2 KCNJ1
241410 HYPOPARATHYROIDISM-RETARDATION-DYSMORPHISM SYNDROME; HRD TBCE
241510 HYPOPHOSPHATASIA, CHILDHOOD ALPL
241520 HYPOPHOSPHATEMIC RICKETS, AR DMP1
241550 HYPOPLASTIC LEFT HEART SYNDROME GJA1
242300 ICHTHYOSIS, LAMELLAR, 1; LI1 TGM1
242500 ICHTHYOSIS CONGENITA, HARLEQUIN FETUS ABCA12
242860 IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME DNMT3B
243500 ISOVALERIC ACIDEMIA; IVA IVD
243800 JOHANSON-BLIZZARD SYNDROME; JBS UBR1
244460 KENNY-CAFFEY SYNDROME, 1; KCS TBCE
245200 KRABBE DISEASE GALC
245349 PYRUVATE DEHYDROGENASE E3-BINDING PROTEIN DEFICIENCY PDHX
245400 LACTIC ACIDOSIS, FATAL INFANTILE SUCLG1
245660 LARYNGOONYCHOCUTANEOUS SYNDROME; LOCS LAMA3
246200 DONOHUE SYNDROME INSR
246450 3-HYDROXY-3-METHYLGLUTARYL-CoA LYASE DEFICIENCY HMGCL
248190 HYPOMAGNESEMIA, RENAL, WITH OCULAR INVOLVEMENT CLDN19
248500 MANNOSIDOSIS, ALPHA B, LYSOSOMAL MAN2B1
248600 MAPLE SYRUP URINE DISEASE Ia BCKDHA
248600 MAPLE SYRUP URINE DISEASE, CLASSIC, IB BCKDHB
248600 MAPLE SYRUP URINE DISEASE III DLD
248800 Marinesco-Sjogren Syndrome SIL1
249000 MECKEL SYNDROME, 1; MKS1 MKS1
249100 FAMILIAL MEDITERRANEAN FEVER; FMF MEFV
249900 METACHROMATIC LEUKODYSTROPHY DUE TO SAPOSIN B DEFICIENCY PSAP
250100 METACHROMATIC LEUKODYSTROPHY ARSA
250250 CARTILAGE-HAIR HYPOPLASIA; CHH RMRP
250620 BETA-HYDROXYISOBUTYRYL CoA DEACYLASE, DEFICIENCY OF HIBCH
250950 3-METHYLGLUTACONIC ACIDURIA, I AUH
251000 METHYLMALONIC ACIDURIA DUE TO METHYLMALONYL-CoA MUTASE DEFICIENCY MUT
251110 METHYLMALONIC ACIDURIA, cblB MMAB
251260 NIJMEGEN BREAKAGE SYNDROME NBN
251880 MITOCHONDRIAL DNA DEPLETION SYNDROME, HEPATOCEREBRAL C10ORF2
251880 MITOCHONDRIAL DNA DEPLETION SYNDROME, HEPATOCEREBRAL DGUOK
251880 MITOCHONDRIAL DNA DEPLETION SYNDROME, HEPATOCEREBRAL MPV17
252150 MOLYBDENUM COFACTOR DEFICIENCY MOCS1
252150 MOLYBDENUM COFACTOR DEFICIENCY MOCS2
252500 MUCOLIPIDOSIS II ALPHA/BETA GNPTAB
252600 MUCOLIPIDOSIS III ALPHA/BETA GNPTAB
252650 MUCOLIPIDOSIS IV MCOLN1
252900 MUCOPOLYSACCHARIDOSIS IIIA SGSH
252930 MUCOPOLYSACCHARIDOSIS IIIC HGSNAT
253200 MUCOPOLYSACCHARIDOSIS VI ARSB
253220 MUCOPOLYSACCHARIDOSIS VII GUSB
253230 MUCOPOLYSACCHARIDOSIS VIII GNS
253250 MULIBREY NANISM TRIM37
253260 BIOTINIDASE DEFICIENCY BTD
253280 MUSCLE-EYE-BRAIN DISEASE; MEB FKRP
253280 MUSCLE-EYE-BRAIN DISEASE; MEB POMGNT1
253290 MULTIPLE PTERYGIUM SYNDROME, LETHAL CHRNA1
253290 MULTIPLE PTERYGIUM SYNDROME, LETHAL CHRND
253290 MULTIPLE PTERYGIUM SYNDROME, LETHAL CHRNG
253300 SPINAL MUSCULAR ATROPHY, I; SMA1 SMN1
253310 LETHAL CONGENITAL CONTRACTURE SYNDROME 1; LCCS1 GLE1
253400 SPINAL MUSCULAR ATROPHY, III; SMA3 SMN1
253550 SPINAL MUSCULAR ATROPHY, II; SMA2 SMN1
253800 FUKUYAMA CONGENITAL MUSCULAR DYSTROPHY; FCMD FKTN
254780 MYOCLONIC EPILEPSY OF LAFORA EPM2A
254780 MYOCLONIC EPILEPSY OF LAFORA NHLRC1
254800 MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG CSTB
255110 CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LATE-ONSET CPT2
255120 CARNITINE PALMITOYLTRANSFERASE I DEFICIENCY CPT1A
255960 MYXOMA, INTRACARDIAC PRKAR1A
256030 NEMALINE MYOPATHY 2; NEM2 NEB
256050 ATELOSTEOGENESIS, II; AOII SLC26A2
256100 NEPHRONOPHTHISIS 1; NPHP1 NPHP1
256300 NEPHROSIS 1, CONGENITAL, FINNISH ; NPHS1 NPHS1
256370 NEPHROTIC SYNDROME, EARLY-ONSET, WITH DIFFUSE MESANGIAL SCLEROSIS WT1
256550 NEURAMINIDASE DEFICIENCY NEU1
256600 NEUROAXONAL DYSTROPHY, INFANTILE; INAD1 PLA2G6
256710 ELEJALDE DISEASE MYO5A
256730 CEROID LIPOFUSCINOSIS, NEURONAL, 1; CLN1 PPT1
256731 CEROID LIPOFUSCINOSIS, NEURONAL, 5; CLN5 CLN5
256800 INSENSITIVITY TO PAIN, CONGENITAL, WITH ANHIDROSIS; CIPA NTRK1
256810 NAVAJO NEUROHEPATOPATHY; NN MPV17
257200 NIEMANN-PICK DISEASE, A SMPD1
257220 NIEMANN-PICK DISEASE, C1; NPC1 NPC1
257320 LISSENCEPHALY 2; LIS2 RELN
257980 ODONTOONYCHODERMAL DYSPLASIA; OODD WNT10A
258501 3-METHYLGLUTACONIC ACIDURIA, III OPA3
259700 OSTEOPETROSIS, AR 1; OPTB1 TCIRG1
259720 OSTEOPETROSIS, AR 5; OPTB5 OSTM1
259730 OSTEOPETROSIS, AR 3; OPTB3 CA2
259770 OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME; OPPG LRP5
259775 RAINE SYNDROME; RNS FAM20C
259900 HYPEROXALURIA, PRIMARY, I AGXT
260000 HYPEROXALURIA, PRIMARY, II GRHPR
260400 SHWACHMAN-DIAMOND SYNDROME; SDS SBDS
261515 D-BIFUNCTIONAL PROTEIN DEFICIENCY HSD17B4
261600 PHENYLKETONURIA; PKU PAH
261740 GLYCOGEN STORAGE DISEASE OF HEART, LETHAL CONGENITAL PRKAG2
262300 ACHROMATOPSIA 3; ACHM3 CNGB3
262600 PITUITARY DWARFISM III HESX1
262600 PITUITARY DWARFISM III LHX3
262600 PITUITARY DWARFISM III POU1F1
262600 PITUITARY DWARFISM III PROP1
263200 POLYCYSTIC KIDNEY DISEASE, AR; ARPKD PKHD1
263700 PORPHYRIA, CONGENITAL ERYTHROPOIETIC UROS
264350 PSEUDOHYPOALDOSTERONISM, I, AR; PHA1 SCNN1A
264350 PSEUDOHYPOALDOSTERONISM, I, AR; PHA1 SCNN1B
264350 PSEUDOHYPOALDOSTERONISM, I, AR; PHA1 SCNN1G
264470 PEROXISOMAL ACYL-CoA OXIDASE DEFICIENCY ACOX1
264700 VITAMIN D-DEPENDENT RICKETS, I CYP27B1
265000 MULTIPLE PTERYGIUM SYNDROME, ESCOBAR CHRNG
265100 PULMONARY ALVEOLAR MICROLITHIASIS SLC34A2
265120 SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 1; SMDP1 SFTPB
265380 NEWBORN PULMONARY HYPERTENSION, FAMILIAL PERSISTENT CPS1
265450 PULMONARY VENOOCCLUSIVE DISEASE; PVOD BMPR2
265800 PYCNODYSOSTOSIS CTSK
266130 GLUTATHIONE SYNTHETASE DEFICIENCY GSS
266150 PYRUVATE CARBOXYLASE DEFICIENCY PC
266200 PYRUVATE KINASE DEFICIENCY OF RED CELLS PKLR
266265 CONGENITAL DISORDER OF GLYCOSYLATION, IIc; CDG2C SLC35C1
266900 SENIOR-LOKEN SYNDROME 1; SLSN1 NPHP1
267430 RENAL TUBULAR DYSGENESIS; RTD ACE
267430 RENAL TUBULAR DYSGENESIS; RTD AGT
267430 RENAL TUBULAR DYSGENESIS; RTD AGTR1
267430 RENAL TUBULAR DYSGENESIS; RTD REN
267450 RESPIRATORY DISTRESS SYNDROME IN PREMATURE INFANTS SFTPA1
267450 RESPIRATORY DISTRESS SYNDROME IN PREMATURE INFANTS SFTPB
267450 RESPIRATORY DISTRESS SYNDROME IN PREMATURE INFANTS SFTPC
268300 ROBERTS SYNDROME; RBS ESCO2
268800 SANDHOFF DISEASE HEXB
269250 SCHNECKENBECKEN DYSPLASIA SLC35D1
269920 INFANTILE SIALIC ACID STORAGE DISORDER SLC17A5
270200 SJOGREN-LARSSON SYNDROME; SLS ALDH3A2
270400 SMITH-LEMLI-OPITZ SYNDROME; SLOS DHCR7
270450 INSULIN-LIKE GROWTH FACTOR I, RESISTANCE TO IGF1
270550 SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY ; SACS SACS
271245 INFANTILE-ONSET SPINOCEREBELLAR ATAXIA; IOSCA C10ORF2
271900 CANAVAN DISEASE ASPA
271930 STRIATONIGRAL DEGENERATION, INFANTILE; SNDI NUP62
271980 SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY ALDH5A1
272300 SULFOCYSTEINURIA SUOX
272800 TAY-SACHS DISEASE; TSD HEXA
273395 TETRA-AMELIA, AR WNT3
274150 THROMBOTIC THROMBOCYTOPENIC PURPURA, CONGENITAL; TTP ADAMTS13
274270 DIHYDROPYRIMIDINE DEHYDROGENASE; DPYD DPYD
274600 PENDRED SYNDROME; PDS SLC26A4
275100 HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 4; CHNG4 TSHB
275210 TIGHT SKIN CONTRACTURE SYNDROME, LETHAL LMNA
275210 TIGHT SKIN CONTRACTURE SYNDROME, LETHAL ZMPSTE24
276700 TYROSINEMIA, I FAH
276820 ULNA AND FIBULA, ABSENCE OF WNT7A
276900 USHER SYNDROME, I MYO7A
276901 USHER SYNDROME, IIA; USH2A USH2A
276902 USHER SYNDROME, III; USH3 CLRN1
276904 USHER SYNDROME, IC; USH1C USH1C
277300 SPONDYLOCOSTAL DYSOSTOSIS, AR 1; SCDO1 DLL3
277400 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC MMACHC
277440 VITAMIN D-DEPENDENT RICKETS, II VDR
277460 VITAMIN E, FAMILIAL ISOLATED DEFICIENCY OF; VED TTPA
277470 PONTOCEREBELLAR HYPOPLASIA 2A; PCH2A TSEN54
277580 WAARDENBURG-SHAH SYNDROME EDN3
277580 WAARDENBURG-SHAH SYNDROME EDNRB
277580 WAARDENBURG-SHAH SYNDROME SOX10
277900 WILSON DISEASE ATP7B
278700 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A; XPA XPA
278730 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D; XPD ERCC2
278740 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP E DDB2
278760 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; XPF ERCC4
278780 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP G; XPG ERCC5
278800 DE SANCTIS-CACCHIONE SYNDROME ERCC6
278800 DE SANCTIS-CACCHIONE SYNDROME XPA
300004 CORPUS CALLOSUM, AGENESIS OF, WITH ABNORMAL GENITALIA ARX
300018 DOSAGE-SENSITIVE SEX REVERSAL; DSS NR0B1
300048 INTESTINAL PSEUDOOBSTRUCTION, NEURONAL, CHRONIC IDIOPATHIC, XLR FLNA
300067 LISSENCEPHALY, XLR, 1; LISX1 DCX
300069 CARDIOMYOPATHY, DILATED, 3A; CMD3A TAZ
300100 ADRENOLEUKODYSTROPHY; ALD ABCD1
300209 SIMPSON-GOLABI-BEHMEL SYNDROME, 2 OFD1
300215 LISSENCEPHALY, XLR, 2 LISX2 ARX
300220 MENTAL RETARDATION, XLR, SYNDROMIC 10; MRXS10 HSD17B10
300240 HOYERAAL-HREIDARSSON SYNDROME; HHS DKC1
300243 MENTAL RETARDATION, XLR, SYNDROMIC, CHRISTIANSON SLC9A6
300291 ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY IKBKG
300301 OSTEOPETROSIS, LYMPHEDEMA, ECTODERMAL DYSPLASIA, ANHIDROSIS, IMMUNODEFICIENCY IKBKG
300322 LESCH-NYHAN SYNDROME; LNS HPRT1
300352 CREATINE DEFICIENCY SYNDROME, XLR SLC6A8
300400 SEVERE COMBINED IMMUNODEFICIENCY, XLR; SCIDX1 IL2RG
300472 AGENESIS OF CORPUS CALLOSUM WITH MENTAL RETARDATION, OCULAR COLOBOMA IGBP1
300523 ALLAN-HERNDON-DUDLEY SYNDROME AHDS SLC16A2
300672 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 2 CDKL5
300673 ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATIONS MECP2
300755 AGAMMAGLOBULINEMIA, XLR XLA BTK
301000 WISKOTT-ALDRICH SYNDROME; WAS WAS
301040 α-THALASSEMIA/MENTAL RETARDATION SYNDROME,NONDELETION , XLR ATRX ATRX
301500 FABRY DISEASE GLA
301830 SPINAL MUSCULAR ATROPHY, XLR 2; SMAX2 UBA1
301835 ARTS SYNDROME; ARTS PRPS1
302045 CARDIOMYOPATHY, DILATED, 3B; CMD3B DMD
302060 BARTH SYNDROME; BTHS TAZ
302950 CHONDRODYSPLASIA PUNCTATA 1, XLR RECESSIVE; CDPX1 ARSE
303100 CHOROIDEREMIA; CHM CHM
303350 MASA SYNDROME L1CAM
304100 CORPUS CALLOSUM, PARTIAL AGENESIS OF, XLR L1CAM
304790 IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, XLR FOXP3
305100 ECTODERMAL DYSPLASIA, HYPOHIDROTIC, XLR; XHED EDA
305900 GLUCOSE-6-PHOSPHATE DEHYDROGENASE; G6PD G6PD
306955 HETEROTAXY, VISCERAL, 1, XLR; HTX1 ZIC3
307000 HYDROCEPHALUS DUE TO CONGENITAL STENOSIS OF AQUEDUCT OF SYLVIUS; HSAS L1CAM
308230 IMMUNODEFICIENCY WITH HYPER-IgM, 1; HIGM1 CD40LG
308240 LYMPHOPROLIFERATIVE SYNDROME, XLR, 1; XLP1 SH2D1A
308350 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 ARX
308370 INFERTILE MALE SYNDROME AR
308930 LEIGH SYNDROME, XLR PDHA1
309000 LOWE OCULOCEREBRORENAL SYNDROME; OCRL OCRL
309400 MENKES DISEASE ATP7A
309500 RENPENNING SYNDROME 1; RENS1 PQBP1
309520 LUJAN-FRYNS SYNDROME MED12
310200 MUSCULAR DYSTROPHY, DUCHENNE ; DMD DMD
310400 MYOTUBULAR MYOPATHY 1; MTM1 MTM1
310600 NORRIE DISEASE; ND NDP
311150 OPTICOACOUSTIC NERVE ATROPHY WITH DEMENTIA TIMM8A
311250 ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO OTC
312060 PROPERDIN DEFICIENCY, XLR CFP
312080 PELIZAEUS-MERZBACHER DISEASE; PMD PLP1
312700 RETINOSCHISIS 1, XLR, JUVENILE; RS1 RS1
312750 RETT SYNDROME; RTT MECP2
312863 COMBINED IMMUNODEFICIENCY, XLR; CIDX IL2RG
312920 SPASTIC PARAPLEGIA 2, XLR; SPG2 PLP1
314390 VACTERL ASSOCIATION WITH HYDROCEPHALUS, XLR FANCB
600060 DEAFNESS, NEUROSENSORY, AR 2; DFNB2 MYO7A
600118 WARBURG MICRO SYNDROME; WARBM RAB3GAP1
600121 RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, 3; RCDP3 AGPS
600143 CEROID LIPOFUSCINOSIS, NEURONAL, 8; CLN8 CLN8
600501 ABCD SYNDROME EDNRB
600649 CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE CPT2
600721 D-2-HYDROXYGLUTARIC ACIDURIA D2HGDH
600737 INCLUSION BODY MYOPATHY 2, AR; IBM2 GNE
600802 SEVERE COMBINED IMMUNODEFICIENCY, AR, T CELL- B CELL+, NK CELL- JAK3
600972 ACHONDROGENESIS, IB; ACG1B SLC26A2
601067 USHER SYNDROME, ID; USH1D CDH23
601186 MICROPHTHALMIA, SYNDROMIC 9; MCOPS9 STRA6
601378 CRISPONI SYNDROME CRLF1
601451 NEVO SYNDROME PLOD1
601457 SEVERE COMBINED IMMUNODEFICIENCY, AR, T CELL-NEGATIVE, RAG1
601457 SEVERE COMBINED IMMUNODEFICIENCY, AR, T CELL-NEGATIVE, RAG2
601559 STUVE-WIEDEMANN SYNDROME LIFR
601675 TRICHOTHIODYSTROPHY, PHOTOSENSITIVE; TTDP ERCC2
601675 TRICHOTHIODYSTROPHY, PHOTOSENSITIVE; TTDP ERCC3
601675 TRICHOTHIODYSTROPHY, PHOTOSENSITIVE; TTDP GTF2H5
601678 BARTTER SYNDROME, ANTENATAL, 1 SLC12A1
601705 T-CELL IMMUNODEFICIENCY, CONGENITAL ALOPECIA, AND NAIL DYSTROPHY FOXN1
601706 YEMENITE DEAF-BLIND HYPOPIGMENTATION SYNDROME SOX10
601780 CEROID LIPOFUSCINOSIS, NEURONAL, 6; CLN6 CLN6
601847 CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC 2; PFIC2 ABCB11
602083 USHER SYNDROME, IF; USH1F PCDH15
602088 NEPHRONOPHTHISIS 2; NPHP2 INVS
602390 HEMOCHROMATOSIS, JUVENILE; JH HAMP
602390 HEMOCHROMATOSIS, JUVENILE; JH HFE2
602398 DESMOSTEROLOSIS DHCR24
602473 ENCEPHALOPATHY, ETHYLMALONIC ETHE1
602579 CONGENITAL DISORDER OF GLYCOSYLATION, Ib; CDG1B MPI
602771 RIGID SPINE MUSCULAR DYSTROPHY 1; RSMD1 SEPN1
603147 CONGENITAL DISORDER OF GLYCOSYLATION, Ic; CDG1C ALG6
603358 GRACILE SYNDROME BCS1L
603554 OMENN SYNDROME DCLRE1C
603554 OMENN SYNDROME RAG1
603554 OMENN SYNDROME RAG2
603585 CONGENITAL DISORDER OF GLYCOSYLATION, IIf; CDG2F SLC35A1
603903 SICKLE CELL ANEMIA HBB
604004 MEGALENCEPHALIC LEUKOENCEPHALOPATHY WITH SUBCORTICAL CYSTS; MLC MLC1
604250 HEMOCHROMATOSIS, 3 TFR2
604320 SPINAL MUSCULAR ATROPHY, DISTAL, AR, 1; DSMA1 IGHMBP2
604369 SIALURIA, FINNISH SLC17A5
604377 CARDIOENCEPHALOMYOPATHY, FATAL INFANTILE, DUE TO CYTOCHROME c OXIDASE SCO2
604498 AMEGAKARYOCYTIC THROMBOCYTOPENIA, CONGENITAL; CAMT MPL
605039 C-LIKE SYNDROME CD96
605253 NEUROPATHY, HYPOMYELINATING/CHARCOT-MARIE-TOOTH DISEASE, 4E EGR2
605253 NEUROPATHY, HYPOMYELINATING/CHARCOT-MARIE-TOOTH DISEASE, 4E MPZ
605355 NEMALINE MYOPATHY 5; NEM5 TNNT1
605407 SEGAWA SYNDROME, AR TH
605472 USHER SYNDROME, IIC; USH2C GPR98
605899 GLYCINE ENCEPHALOPATHY; GCE AMT
605899 GLYCINE ENCEPHALOPATHY; GCE GCSH
605899 GLYCINE ENCEPHALOPATHY; GCE GLDC
606056 CONGENITAL DISORDER OF GLYCOSYLATION, IIb; CDG2B MOGS
606353 PRIMARY LATERAL SCLEROSIS, JUVENILE; PLSJ ALS2
606369 EPILEPTIC ENCEPHALOPATHY, LENNOX-GASTAUT MAPK10
606407 HYPOTONIA-CYSTINURIA SYNDROME PREPL
606407 HYPOTONIA-CYSTINURIA SYNDROME SLC3A1
606612 MUSCULAR DYSTROPHY, CONGENITAL, 1C; MDC1C FKRP
606812 FUMARASE DEFICIENCY FH
606943 USHER SYNDROME, IG; USH1G USH1G
606966 NEPHRONOPHTHISIS 4; NPHP4 NPHP4
607014 HURLER SYNDROME IDUA
607091 CONGENITAL DISORDER OF GLYCOSYLATION, IId; CDG2D B4GALT1
607095 ANAUXETIC DYSPLASIA RMRP
607330 LATHOSTEROLOSIS SC5DL
607426 COENZYME Q10 DEFICIENCY APTX
607426 COENZYME Q10 DEFICIENCY CABC1
607426 COENZYME Q10 DEFICIENCY COQ2
607426 COENZYME Q10 DEFICIENCY PDSS1
607426 COENZYME Q10 DEFICIENCY PDSS2
607598 ICOS DEFICIENCY; LCCS2 ERBB3
607616 NIEMANN-PICK DISEASE, B SMPD1
607624 GRISCELLI SYNDROME, 2; GS2 RAB27A
607625 NIEMANN-PICK DISEASE, C2 NPC2
607626 ICHTHYOSIS, LEUKOCYTE VACUOLES, ALOPECIA, AND SCLEROSING CHOLANGITIS CLDN1
607655 SKIN FRAGILITY-WOOLLY HAIR SYNDROME DSP
607855 MUSCULAR DYSTROPHY, CONGENITAL MEROSIN-DEFICIENT, 1A; MDC1A LAMA2
608013 GAUCHER DISEASE, PERINATAL LETHAL GBA
608093 CONGENITAL DISORDER OF GLYCOSYLATION, Ij; CDG1J DPAGT1
608099 MUSCULAR DYSTROPHY, LIMB-GIRDLE, 2D; LGMD2D SGCA
608456 COLORECTAL ADENOMATOUS POLYPOSIS, AR MUTYH
608540 CONGENITAL DISORDER OF GLYCOSYLATION, Ik; CDG1K ALG1
608612 MANDIBULOACRAL DYSPLASIA WITH B LIPODYSTROPHY; MADB ZMPSTE24
608629 JOUBERT SYNDROME 3; JBTS3 AHI1
608643 AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY DDC
608688 AICAR TRANSYLASE/IMP CYCLOHYDROLASE, DEFICIENCY OF ATIC
608782 PYRUVATE DEHYDROGENASE PHOSPHATASE DEFICIENCY PDP1
608799 CONGENITAL DISORDER OF GLYCOSYLATION, Ie; CDG1E DPM1
608800 SUDDEN INFANT DEATH WITH DYSGENESIS OF THE TESTES SYNDROME; SIDDT TSPYL1
608804 LEUKODYSTROPHY, HYPOMYELINATING, 2 GJC2
608836 CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL CPT2
608840 MUSCULAR DYSTROPHY, CONGENITAL, 1D LARGE
609015 TRIFUNCTIONAL PROTEIN DEFICIENCY HADHA
609015 TRIFUNCTIONAL PROTEIN DEFICIENCY HADHB
609016 LONG-CHAIN 3-HYDROXYACYL-CoA DEHYDROGENASE DEFICIENCY HADHA
609049 PIERSON SYNDROME LAMB2
609056 AMISH INFANTILE EPILEPSY SYNDROME ST3GAL5
609060 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1 GFM1
609241 SCHINDLER DISEASE, I NAGA
609254 SENIOR-LOKEN SYNDROME 5; SLSN5 IQCB1
609304 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 3 SLC25A22
609311 CHARCOT-MARIE-TOOTH DISEASE, 4H; CMT4H FGD4
609528 CEREBRAL DYSGENESIS, NEUROPATHY, ICHTHYOSIS, PALMOPLANTAR KERATODERMA SNAP29
609560 MITOCHONDRIAL DNA DEPLETION SYNDROME, MYOPATHIC TK2
609583 JOUBERT SYNDROME 4; JBTS4 NPHP1
609638 EPIDERMOLYSIS BULLOSA, LETHAL ACANTHOLYTIC DSP
610003 CEROID LIPOFUSCINOSIS, NEURONAL, 8, NORTHERN EPILEPSY CLN8
610006 2-METHYLBUTYRYL-CoA DEHYDROGENASE DEFICIENCY ACADSB
610090 PYRIDOXAMINE 5-PRIME-PHOSPHATE OXIDASE DEFICIENCY PNPO
610127 CEROID LIPOFUSCINOSIS, NEURONAL, 10; CLN10 CTSD
610188 JOUBERT SYNDROME 5; JBTS5 CEP290
610198 3-METHYLGLUTACONIC ACIDURIA, V DNAJC19
610370 DIARRHEA 4, MALABSORPTIVE, CONGENITAL NEUROG3
610377 MEVALONIC ACIDURIA MVK
610498 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 2; COXPD2 MRPS16
610505 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 3; COXPD3 TSFM
610532 LEUKODYSTROPHY, HYPOMYELINATING, 5 FAM126A
610651 XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP B; XPB ERCC3
610688 JOUBERT SYNDROME 6; JBTS6 TMEM67
610725 NEPHROTIC SYNDROME, 3; NPHS3 PLCE1
610768 CONGENITAL DISORDER OF GLYCOSYLATION, Im; CDG1M DOLK
610854 OSTEOGENESIS IMPERFECTA, IIB CRTAP
610915 OSTEOGENESIS IMPERFECTA, VIII LEPRE1
610951 CEROID LIPOFUSCINOSIS, NEURONAL, 7; CLN7 MFSD8
610992 PHOSPHOSERINE AMINOTRANSFERASE DEFICIENCY PSAT1
611067 SPINAL MUSCULAR ATROPHY, DISTAL, AR, 4; DSMA4 PLEKHG5
611126 ACYL-CoA DEHYDROGENASE FAMILY, MEMBER 9, DEFICIENCY OF ACAD9
611561 MECKEL SYNDROME, 5; MKS5 RPGRIP1L
611705 MYOPATHY, EARLY-ONSET, WITH FATAL CARDIOMYOPATHY TTN
611719 COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 5; COXPD5 MRPS22
611721 COMBINED SAPOSIN DEFICIENCY PSAP
611722 KRABBE DISEASE, ATYPICAL, DUE TO SAPOSIN A DEFICIENCY PSAP
611726 EPILEPSY, PROGRESSIVE MYOCLONIC 3; EPM3 KCTD7
612164 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4 STXBP1
612304 THROMBOPHILIA, HEREDITARY, DUE TO PROTEIN C DEFICIENCY, AUTOSOMAL PROC
612416 FACTOR XI DEFICIENCY F11
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Competing Interests

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

Acknowledgments

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.

Biography

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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