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Am J Med Genet A. Author manuscript; available in PMC 2013 December 1.
Published in final edited form as:
PMCID: PMC3507421
NIHMSID: NIHMS399421

Clinical Geneticists’ Views of VACTERL/VATER Association

Abstract

VACTERL association (sometimes termed “VATER association” depending on which component features are included) is typically defined by the presence of at least three of the following congenital malformations, which tend to statistically co-occur in affected individuals: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Although the clinical criteria for VACTERL association may appear to be straightforward, there is wide variability in the way clinical geneticists define the disorder and the genetic testing strategy they use when confronted with an affected patient. In order to describe this variability and determine the most commonly used definitions and testing modalities, we present the results of survey responses by 121 clinical geneticists. We discuss the results of the survey responses, provide a literature review and commentary from a group of physicians who are currently involved in clinical and laboratory-based research on VACTERL association, and offer an algorithm for genetic testing in patients with this association.

Keywords: VACTERL association, VATER association

INTRODUCTION

VATER association was originally named in the early 1970s with the description of seven patients as including at least three of the following features: Vertebral defects, Anal atresia, Tracheo-Esophageal fistula, Radial and Renal dysplasia [Quan and Smith, 1973]. Shortly thereafter, additional features, such as Cardiac malformations and additional Limb abnormalities, were added, and the condition was called VACTERL association, which remains the more prevalent term according to our survey (we will use this term in the remainder of this article) [Quan and Smith 1973; Nora and Nora, 1973; Temtamy and Miller, 1974; Nora and Nora, 1975; Khoury et al., 1983; Czeizel and Ludányi, 1985, Rittler et al., 1996]. As described in detail below, the precise definition has remained uncertain, at least partially because of a lack of uniform population-based studies that support the early descriptions.

VACTERL association is estimated to occur in approximately 1 in 10,000 to 1 in 40,000 live-born infants, depending on the exact criteria and the type of ascertainment used [Khoury et al., 1983; Czeizel and Ludányi, 1985; Botto et al., 1997]. Despite the original descriptions almost four decades ago, relatively little is known about the etiology of VACTERL association [reviewed in Solomon, 2011].

The authors of this article comprise a group of physicians who are all currently involved in clinical and laboratory-based research on VACTERL association and related conditions. We are aware that a wide range of opinions exists with regards to howVACTERL association is defined and what diagnostic genetic tests should be requested in patients with this association. In order to determine how practicing clinical geneticists view this condition and what genetic tests are typically ordered, we surveyed a cohort of clinical geneticists who provide medical services to individuals with VACTERL association. In this article, we present and discuss data obtained from 121 respondents. The results of this survey demonstrate a wide variability in the way physicians approach the diagnostic evaluation and genetic testing of individuals with VACTERL association. In some cases, these results can be used to determine the “mainstream” approach. In addition to commenting on the results of the survey, we provide in the Discussion, a review of the literature on certain salient issues raised in this study, as well as a detailed differential diagnosis of testable conditions that may be considered when encountering an affected patient.

MATERIALS AND METHODS

An invitation to participate in this study, containing a link to a free online survey, was sent via email to a cohort of practicing physician clinical geneticists. The survey consisted of a combination of open and closed-ended questions (see Supplementary material in Supporting Information online for an exact transcript of the questions in the online survey). The email was sent to current and previous participants of the David W. Smith Workshop on Malformations and Morphogenesis, and participants were told that they could also forward the invitation to their physician clinical geneticist colleagues. Additionally, each of the article’s co-authors sent the invitation to physician colleagues at their institutions and other potential respondents.

RESULTS

The results of the survey responses are presented in tabular format, and are summarized here as well. The data have been divided into the following tables: demographic data (Table I); definitions and diagnostic criteria (Table II); testing approach (Table III); information related to Fanconi anemia testing (Table IV).

Table I
Demographic information for 121 survey respondents.
Table II
Definitions and diagnostic criteria.
Table III
Testing approach.
Table IV
Data related to Fanconi anemia testing attitudes.

We analyzed results from 121 respondents; although most (61%) are based in the United States, the remainder (39%) represents 14 different countries. Approximately 10% are physicians still in genetics-training programs. The experience of the remaining 90% of respondents ranges from immediate post-training to over 20 years of medical genetics experience; the latter category represents the single largest group of respondents (26% of the total) (Table I).

As expected, there was a wide range of responses in terms of how the condition is termed, defined, and what testing is offered (Table II). Most respondents call the condition “VACTERL” association (64%) and require at least three component features to be present (79%). Among component features, vertebral anomalies, anal atresia, and tracheo-esophageal fistula were included as defining in at least 90% of respondents. Cardiac malformations, renal anomalies, and limb abnormalities were all considered to be defining features by less than 90%. In addition to the core component features, some respondents consider other features to be defining, including other anomalies (eg, genitourinary) and the presence of spatially disparate malformations. A majority of respondents indicated that the presence of non-classic features, such as dysmorphic facial features (79%), or unexplained cognitive impairment (80%), would alter the diagnostic impression.

Just as there is great variability in the definition and diagnostic features used, there is a wide spectrum in terms of genetic work-up typically initiated when clinical geneticists encounter a patient with VACTERL association (Table III). Microarray analysis is the single most common test used in both the prenatal (56%) and postnatal (86%) settings, followed by routine karyotype, Fanconi anemia testing, and single-gene testing.

As Fanconi anemia can be associated with significant medical complications, we inquired about how often respondents test for this condition, and what typically leads to such testing (Table IV). Unsurprisingly, many different responses were given related to what triggers Fanconi anemia testing. Interestingly, approximately two-thirds of respondents either never test for this condition, or test for this condition less than 25% of the time.

DISCUSSION

The results of this survey demonstrate the wide range of opinions held by clinical geneticists who care for patients with VACTERL association. Using data from both our survey and the literature, we address several key issues.

How should the condition be described and defined?

In terms of the number of component features required, the presence of at least 3 component features of VACTERL association is still most commonly used. However, our study (as well as some publications) shows that this requirement is not universally accepted [Weaver et al., 1986; Wheeler and Weaver, 2005; Aguinaga et al., 2010; Källén et al., 2001; Solomon et al., 2010a]. Seventy-nine percent of respondents required at least three component features (7% required at least four), while 15% required only at least two component features. An alternate approach mentioned by several survey respondents, which may have some credence, is the requirement of a “core” feature, in which the presence of certain component features would be weighted more heavily in the others. In the literature, this approach has been suggested for anorectal malformations or tracheo-esophageal fistula as such core features [Jenetzky et al., 2011].

It should be noted that in terms of the specific component features included in the definition, the presence of congenital heart malformations as well as other “vascular” anomalies such as single umbilical artery, were added shortly after the initial description based on further cohorts of analyzed patients and studies of possibly associated teratogens and [Nora and Nora, 1973; Temtamy and Miller, 1974; Nora and Nora 1975]. However, later statistical analyses of larger cohorts cast doubt about the inclusion of some features, such as cardiac malformations or renal anomalies, and provided some evidence that only certain types of limb abnormalities (such as upper limb radial/preaxial reduction abnormalities) should be included [Rittler et al., 1996; Botto et al., 1997; Källén et al., 2001].

As our survey results indicate, cardiac malformations, renal anomalies, and limb abnormalities are less frequently considered to be defining component features (these are considered to be defining features by 82%, 85%, and 71% of respondents, respectively, versus vertebral anomalies, anal atresia, and tracheo-esophageal fistula, all of which were considered to be defining features by at least 90% of respondents), reflecting the uncertainty in the literature.

To further complicate the picture, there is also evidence that other component features not traditionally included in the VACTERL acronym can be supportive, such as single umbilical artery, genitourinary anomalies, or spatially disparate findings, as mentioned by some respondents [de Jong et al., 2008; de Jong et al., 2010a; Solomon et al., 2010a; Solomon et al., 2011c].

Much of the confusion in terms of exactly what should be incorporated in the definition is likely due to the fact that a high level of etiological heterogeneity is likely to be present among individuals with VACTERL association [Evans et al., 1985; Evans et al., 1992; Botto et al., 1997; Solomon et al., 2010a]. As our ability to identify the underlying etiologies of individuals with VACTERL association improves, it is likely that patients will be subdivided into molecularly-defined groups representing discrete disorders. As that occurs, concerns over the exact number and type of malformations that should be used to define an individual as having VACTERL association will become less important than the identification of specific signs could be used to guide physicians in their choice of diagnostic tests.

What genetic tests should be considered in a patient with VACTERL association?

Our results show that just as there is a wide range in how VACTERL association is defined, there is also high variability in terms of the clinical approach to genetic testing. This variability may be due, at least in part, to the variation in medical experience and familiarity with this disorder seen in our cohort as well the variation in the availability of various testing modalities available to respondents.

Prenatal setting

As in the postnatal setting, the first step in the evaluation of a patient involves a thorough clinical work-up to determine the number and type of congenital malformations. While detailed examination is naturally more challenging in the prenatal setting, clues for alternative diagnoses should be carefully sought at the outset, with testing directed accordingly. A careful family and medical history (including questions related to potential teratogens, including maternal hyperglycemia, as several survey respondents mentioned) is key, and may best be conducted by a clinical geneticist [reviewed in Solomon, 2011; de Jong et al., 2010b].

Though overall becoming less prevalent in many situations, due to the availability of newer techniques, the karyotype can be a useful, and relatively inexpensive, test to identify aneuploidy, large, cytogenetically-detectable copy number variations, and chromosomal rearrangements that can cause malformations seen in VACTERL association. Over half of survey respondents suggested that they would request a karyotype in the prenatal work up of a fetus with anomalies suggestive of VACTERL association. However, the majority of these respondents would also use other testing modalities including copy number analyses by microarray.

The use of microarrays to detect copy number abnormalities is becoming more common in the prenatal setting, and some series describe clinically relevant findings in setting of prenatal patients with congenital anomalies [Tyreman et al., 2009]. In the prenatal setting, variants of unknown significance can raise complex issues related to reproductive decision making. Indeed, our survey shows that 56% of respondents would use microarray analyses in prenatal setting with 28% of respondents using microarray analyses as the only genetic test. Another strategy that some survey respondents indicated was the use of targeted testing for deletion 22q11.2, especially in the context of cardiac anomalies.

Postnatal testing

From our experience with the clinical work-up of patients with VACTERL association, we suggest the algorithm presented in Figure 1, along with Table V, for the work-up of patients with features of VACTERL association who present to the clinic (Figure 1). In all such situations, the first step is a thorough and careful clinical work-up - including family history - to determine the presence and type of anomalies that may suggest a particular genetic disorder [Solomon et al., 2010a; Solomon et al., 2010b].

Figure 1
Suggested algorithm for the molecular work-up of patients with features of VACTERL association seen in the postnatal setting (see also Table V). The first step involves thorough medical and family history and a detailed physical examination, as well as ...
Table V
Specific conditions in which mutations have been identified that may cause features that overlap VACTERL association. The degree of overlap with “classic” VACTERL association (if such a term might be used) is highly variable, and certain ...

In the absence of a clinically or molecularly identifiable syndrome, copy number analysis by microarray should be considered a first-tier test in patients with congenital anomalies [Miller et al., 2010]. By way of etiological explanation, VACTERL association includes several relatively severe malformations. These malformations were associated with a high rate of lethality in the newborn period until relatively recently, such that affected individuals often did not survive to reproduce. Thus, for the disorder to recur in the population, causes may include highly penetrant de novo events (such as array-detectable aberrations), rare recessive mutations, as well as a multifactorial etiology involving multiple interacting genetic and environmental insults. Thus, array-based testing appears warranted (as does research examining recessive and de novo mutations) as a way to test for one of these explanations. In fact, reports of patients with VACTERL-type anomalies secondary to genomic imbalances supports this recommendation [Walsh et al., 2001; reviewed in Felix et al., 2009; Arrington et al., 2010; de Jong et al., 2010a; de Jong et al., 2010b; Schramm et al., 2011; Solomon et al., 2011c]. Survey respondents indicate this general trend, with 44% of respondents typically performing microarray only, with an additional 42% indicating the selection of a microarray along with other genetic testing.

In cohorts followed by the authors, the use of microarray analysis has been shown to reveal potentially pathogenic aberrations in a small but significant number of individuals, some of whom have been previously reported [de Jong et al., 2010a; Solomon et al., 2011b]. From estimates from several currently-followed cohorts (including over 100 well-phenotyped individuals with VACTERL association) high-density single nucleotide polymorphism (SNP) microarray (>1 million SNPs) showed de novo aberrations likely associated with disease in 3–5% of tested individuals. However, as the inheritance of VACTERL association remains unclear, it is also highly possible that familial array-detected copy number variations may also contribute in a more complex disease model involving incomplete penetrance and multiple interacting factors [Solomon et al., 2010b; Bartels et al., 2012], As with other etiological aspects, when the causes of VACTERL association are further unraveled, reanalysis of existing microarray data sets may be informative.

Unusual features or Mendelian inheritance patterns may provide impetus for single gene testing. For example, alveolar capillary dysplasia should prompt testing of the FOXF1 gene [Stankiewicz et al., 2009]. Approximately 80% of survey respondents indicated that dysmorphic facial features or otherwise unexplained neurocognitive impairment would alter the diagnostic impression. These “red flags” (as well as other findings not usually seen in VACTERL association) may serve as clues for the presence of conditions that include features of VACTERL association (see Table V). For each overlapping condition, many of which have testing available, clinical clues can help determine the likelihood of each, and testing may be important for prognostic discussions and reproductive decision-making.

As an interesting side note, it is clear that VACTERL association is heterogeneous, and it is likely that more identified causes will emerge in the near future. Known etiologies of VACTERL association and overlapping conditions, in conjunction with biological models, have long implicated several key signaling pathways and gene families, such as the Sonic Hedgehog signaling pathway, WNT signaling, and the HOX gene clusters [Mortlock and Innis, 1997; Kim et al., 2001; Biason-Lauber et al., 2004; Johnston et al., 2005; Garcia-Barcelo et al., 2008; Person et al., 2010]. Indeed, genes implicated in related conditions (as shown in Table V) reinforce this observation, and indicate that these signaling pathways may be fruitful to interrogate further. However, it is important to point out in this context that both observed patterns of inheritance and epidemiological factors as well as recent studies showing the plausibility of an environmental insult imposed on a genetic susceptibility indicate that the etiologies contributing to VACTERL association may in many situations be complex [de Jong et al., 2008; Solomon et al., 2010b; Bartels et al., 2012; Sparrow et al., 2012]

Fanconi anemia appears to be a rare cause of features observed in VACTERL association, but it is an important part of the differential diagnosis. This condition deserves special attention because of testing availability and associated morbidity and mortality of the disease. Our survey shows that Fanconi anemia testing is not frequently performed in patients with VACTERL association, with almost two-thirds of responders indicating they never ordered Fanconi anemia testing or ordered it in less than 25% of cases. In one review of over 200 patients with Fanconi anemia, approximately 5% were judged to have VACTERL association [Faivre et al., 2005]. More importantly, another report of 370 patients showed that, at diagnosis, over 16% of patients manifested with congenital malformations but no hematologic abnormalities [Giampietro et al., 1993]. There is little data describing the converse, and more central, question in this context: the prevalence of Fanconi anemia in cohorts of patients ascertained because of the presence of VACTERL association. Data from our cohorts reveal an extremely low rate of positive testing for Fanconi anemia in individuals ascertained primarily because of the cause of VACTERL association In over 100 patients tested via chromosomal breakage assays (e.g., DEB assay), no patients had Fanconi anemia, though one had a myelodysplastic phenotype greatly heightening the index of suspicion, and further testing (from skin biopsy) is currently being performed to test for mosaicism.

As is evident from Table V, while Fanconi anemia is often immediately considered in patients with VACTERL association findings and hematologic and/or oncologic manifestations, other conditions can include both groups of features. Important conditions in the differential diagnosis include both Diamond-Blackfan anemia and Thrombocytopenia-absent radius syndrome [Greenhalgh et al., 2002; Griesinger et al., 2005; Doherty et al., 2010; Vlachos and Muir, 2010; Albers et al., 2012].

Nevertheless, testing for Fanconi anemia is relatively efficient and economical, and the diagnosis is especially important as Fanconia anemia can result in severe hematologic anomalies and predisposition to malignancy. For the purposes of review, findings in patients with Fanconi anemia include any physical anomaly (60%), microsomia (40%), skin anomalies (40%), unilateral or bilateral upper limb abnormalities (35%), microcephaly or hydrocephalus (20%), ocular anomalies (20%), renal anomalies (20%), cognitive impairment (10%), and ear anomalies (10%) [reviewed and much more completely presented in Shimamura and Alter, 2010]. We would, however, suggest that Fanconi anemia testing be considered more often than is currently the case according to our survey results.

As a technical note, there are two cytogenetic assays that can be used to test for Fanconi anemia (using either or both diepoxybutane or mitomycin C, as the latter tends to result in more variable background results) [Cervenka et al., 1981; Auerbach, 1993]. Logistically, the choice of assay type may be limited by availability. Targeted molecular testing is challenging due to locus heterogeneity, but might be considered after cytogenetic diagnosis or in certain situations, such as the case in a known family mutation. Array-based diagnosis has also been described in an instance of X-linked Fanconi anemia manifesting as classic VACTERL-association findings in a neonate [Umaña et al., 2011].

This study has several limitations. First, analysis of results from 121 respondents offers only a small proportion of the opinions of practicing clinical geneticists, and does not include others who may be involved in the early diagnosis and medical management, such as obstetricians, neonatologists, and surgeons. Additionally, emphasizing participants in a specific genetics workshop may skew the results. Second, the survey was relatively short (in order to help maximize respondents’ willingness to participate), and did not explore issues in depth. Finally, while the use of both open and close-ended questions can be helpful in order to capture responses, this can cause challenges in terms of tabulating and considering the overall results of the survey.

In conclusion, modern genomic techniques coupled with the ability to perform complex dissections of environmental insults acting on a background of genetic/genomic susceptibility do offer promise for a better understanding of VACTERL association in the near future. In order to expedite knowledge regarding this condition, we recommend that clinicians avail themselves of publicly accessible databases, such as www.clinicaltrials.gov, in order to find appropriate research referrals (as several survey respondents mentioned) when the etiology remains elusive.

Supplementary Material

Supplementary material

Acknowledgments

The authors would like to extend their gratitude to all study participants. This research was supported by the National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, United States of America (BDS, KAB), and Doris Duke Charitable Foundation grant 2007053 (DAS). Pertaining to Dr. Bear, the views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Army, nor the US Government. Dr. Solomon would like to thank Dr. Max Muenke for his support.

References

  • Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002;71:1195–119. [PubMed]
  • Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007;44:1–9. [PMC free article] [PubMed]
  • Aguinaga M, Zenteno JC, Pérez-Cano H, Morán V. Sonic hedgehog mutation analysis in patients with VACTERL association. Am J Med Genet A. 2010;152A:781–783. [PubMed]
  • Albers CA, Paul DS, Schulze H, Freson K, Stephens JC, Smethurst PA, Jolley JD, Cvejic A, Kostadima M, Bertone P, Breuning MH, Debili N, Deloukas P, Favier R, Fiedler J, Hobbs CM, Huang N, Hurles ME, Kiddle G, Krapels I, Nurden P, Ruivenkamp CA, Sambrook JG, Smith K, Stemple DL, Strauss G, Thys C, van Geet C, Newbury-Ecob R, Ouwehand WH, Ghevaert C. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat Genet. 2012;44:435–439. [PMC free article] [PubMed]
  • Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL, Jr, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002;71:663–668. [PubMed]
  • Arrington CB, Patel A, Bacino CA, Bowles NE. Haploinsufficiency of the LIM domain containing preferred translocation partner in lipoma (LPP) gene in patients with tetralogy of Fallot and VACTERL association. Am J Med Genet A. 2010;152A:2919–2923. [PubMed]
  • Asai-Coakwell M, French CR, Ye M, Garcha K, Bigot K, Perera AG, Staehling-Hampton K, Mema SC, Chanda B, Mushegian A, Bamforth S, Doschak MR, Li G, Dobbs MB, Giampietro PF, Brooks BP, Vijayalakshmi P, Sauvé Y, Abitbol M, Sundaresan P, van Heyningen V, Pourquié O, Underhill TM, Waskiewicz AJ, Lehmann OJ. Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes. Hum Mol Genet. 2009;18:1110–1121. [PubMed]
  • Auerbach AD. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol. 1993;21:731–733. [PubMed]
  • Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res. 2009;668:4–10. [PMC free article] [PubMed]
  • Bamshad M, Lin RC, Law DJ, Watkins WC, Krakowiak PA, Moore ME, Franceschini P, Lala R, Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A, Seidman JG, Seidman CE, Jorde LB. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet. 1997;16:311–315. [PubMed]
  • Bartels E, Jenetzky E, Solomon BD, Ludwig M, Schmiedeke E, Grasshoff-Derr S, Schmidt D, Märzheuser S, Hosie S, Weih S, Holland-Cunz S, Palta M, Leonhardt J, Schäfer M, Kujath C, Rißmann A, Nöthen MM, Reutter H, Zwink N. Inheritance of the VATER/VACTERL association. Pediatr Surg Int. 2012;28:681–685. [PubMed]
  • Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet. 1997;15:30–35. [PubMed]
  • Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46, XX woman. N Engl J Med. 2004;351:792–798. [PubMed]
  • Botto LD, Khoury MJ, Mastroiacovo P, Castilla EE, Moore CA, Skjaerven R, Mutchinick OM, Borman B, Cocchi G, Czeizel AE, Goujard J, Irgens LM, Lancaster PA, Martínez-Frías ML, Merlob P, Ruusinen A, Stoll C, Sumiyoshi Y. The spectrum of congenital anomalies of the VATER association: an international study. Am J Med Genet. 1997;71:8–15. [PubMed]
  • Cervenka J, Arthur D, Yasis C. Mitomycin C test for diagnostic differentiation of idiopathic aplastic anemia and Fanconi anemia. Pediatrics. 1981;67:119–127. [PubMed]
  • Chung B, Shaffer LG, Keating S, Johnson J, Casey B, Chitayat D. From VACTERL-H to heterotaxy: variable expressivity of ZIC3-related disorders. Am J Med Genet A. 2011;155A:1123–1128. [PubMed]
  • Czeizel A, Ludányi I. An aetiological study of the VACTERL-association. Eur J Pediatr. 1985;144:331–337. [PubMed]
  • Davies NP, Imbrici P, Fialho D, Herd C, Bilsland LG, Weber A, Mueller R, Hilton-Jones D, Ealing J, Boothman BR, Giunti P, Parsons LM, Thomas M, Manzur AY, Jurkat-Rott K, Lehmann-Horn F, Chinnery PF, Rose M, Kullmann DM, Hanna MG. Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation. Neurology. 2005;65:1083–1089. [PubMed]
  • De Falco F, Cainarca S, Andolfi G, Ferrentino R, Berti C, Rodríguez Criado G, Rittinger O, Dennis N, Odent S, Rastogi A, Liebelt J, Chitayat D, Winter R, Jawanda H, Ballabio A, Franco B, Meroni G. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A. 2003;120A:222–228. [PubMed]
  • de Jong EM, Douben H, Eussen BH, Felix JF, Wessels MW, Poddighe PJ, Nikkels PG, de Krijger RR, Tibboel D, de Klein A. 5q11.2 deletion in a patient with tracheal agenesis. Eur J Hum Genet. 2010a;18:1265–1268. [PMC free article] [PubMed]
  • de Jong EM, Felix JF, Deurloo JA, van Dooren MF, Aronson DC, Torfs CP, Heij HA, Tibboel D. Non-VACTERL-type anomalies are frequent in patients with esophageal atresia/tracheo-esophageal fistula and full or partial VACTERL association. Birth Defects Res A Clin Mol Teratol. 2008;82:92–97. [PubMed]
  • de Jong EM, Felix JF, de Klein A, Tibboel D. Etiology of esophageal atresia and tracheoesophageal fistula: “mind the gap” Curr Gastroenterol Rep. 2010b;12:215–222. [PMC free article] [PubMed]
  • de Jong EM, de Haan MA, Gischler SJ, Hop W, Cohen-Overbeek TE, Bax NM, de Klein A, Tibboel D, Grijseels EW. Pre- and postnatal diagnosis and outcome of fetuses and neonates with esophageal atresia and tracheoesophageal fistula. Prenat Diagn. 2010c;30:274–279. [PubMed]
  • Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodríguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, Krantz ID. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007;80:485–494. [PubMed]
  • Deveault C, Billingsley G, Duncan JL, Bin J, Theal R, Vincent A, Fieggen KJ, Gerth C, Noordeh N, Traboulsi EI, Fishman GA, Chitayat D, Knueppel T, Millán JM, Munier FL, Kennedy D, Jacobson SG, Innes AM, Mitchell GA, Boycott K, Héon E. BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition. Hum Mutat. 2011;32:610–619. [PubMed]
  • Doherty L, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Clinton C, Schneider HE, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Glader B, Arceci RJ, Farrar JE, Atsidaftos E, Lipton JM, Gleizes PE, Gazda HT. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86:222–228. [PubMed]
  • Evans JA, Reggin J, Greenberg C. Tracheal agenesis and associated malformations: a comparison with tracheoesophageal fistula and the VACTERL association. Am J Med Genet. 1985;21:21–38. [PubMed]
  • Evans JA, Vitez M, Czeizel A. Patterns of acrorenal malformation associations. Am J Med Genet. 1992;44:413–419. [PubMed]
  • Eyaid W, Al-Qattan MM, Al Abdulkareem I, Fetaini N, Al Balwi M. A novel homozygous missense mutation (c.610G>A, p.Gly204Ser) in the WNT7A gene causes tetra-amelia in two Saudi families. Am J Med Genet A. 2011;155A:599–604. [PubMed]
  • Faivre L, Portnoï MF, Pals G, Stoppa-Lyonnet D, Le Merrer M, Thauvin-Robinet C, Huet F, Mathew CG, Joenje H, Verloes A, Baumann C. Should chromosome breakage studies be performed in patients with VACTERL association? Am J Med Genet A. 2005;137:55–58. [PubMed]
  • Felix JF, de Jong EM, Torfs CP, de Klein A, Rottier RJ, Tibboel D. Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: an overview of the current concepts. Birth Defects Res A Clin Mol Teratol. 2009;85:747–754. [PubMed]
  • Garcia-Barceló MM, Wong KK, Lui VC, Yuan ZW, So MT, Ngan ES, Miao XP, Chung PH, Khong PL, Tam PK. Identification of a HOXD13 mutation in a VACTERL patient. Am J Med Genet A. 2008;146A:3181–3185. [PubMed]
  • Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD. The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry. Pediatrics. 1993;91:1116–1120. [PubMed]
  • Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, Innis JW, Holmes LB, Donnenfeld AE, Feingold M, Beemer FA, Hennekam RC, Scambler PJ. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet. 2000;67:197–202. [PubMed]
  • Greenhalgh KL, Howell RT, Bottani A, Ancliff PJ, Brunner HG, Verschuuren-Bemelmans CC, Vernon E, Brown KW, Newbury-Ecob RA. Thrombocytopenia-absent radius syndrome: a clinical genetic study. J Med Genet. 2002;39:876–881. [PMC free article] [PubMed]
  • Griesinger G, Dafopoulos K, Schultze-Mosgau A, Schroder A, Felberbaum R, Diedrich K. Mayer-Rokitansky-Kuster-Hauser syndrome associated with thrombocytopenia-absent radius syndrome. Fertil Steril. 2005;83:452–454. [PubMed]
  • Hagan DM, Ross AJ, Strachan T, Lynch SA, Ruiz-Perez V, Wang YM, Scambler P, Custard E, Reardon W, Hassan S, Nixon P, Papapetrou C, Winter RM, Edwards Y, Morrison K, Barrow M, Cordier-Alex MP, Correia P, Galvin-Parton PA, Gaskill S, Gaskin KJ, Garcia-Minaur S, Gereige R, Hayward R, Homfray T. Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene. Am J Hum Genet. 2000;66:1504–1515. [PubMed]
  • Heinz-Erian P, Müller T, Krabichler B, Schranz M, Becker C, Rüschendorf F, Nürnberg P, Rossier B, Vujic M, Booth IW, Holmberg C, Wijmenga C, Grigelioniene G, Kneepkens CM, Rosipal S, Mistrik M, Kappler M, Michaud L, Dóczy LC, Siu VM, Krantz M, Zoller H, Utermann G, Janecke AR. Mutations in SPINT2 cause a syndromic form of congenital sodium diarrhea. Am J Hum Genet. 2009;84:188–196. [PubMed]
  • Jadeja S, Smyth I, Pitera JE, Taylor MS, van Haelst M, Bentley E, McGregor L, Hopkins J, Chalepakis G, Philip N, Perez Aytes A, Watt FM, Darling SM, Jackson I, Woolf AS, Scambler PJ. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat Genet. 2005;37:520–525. [PubMed]
  • Jenetzky E, Wijers CH, Marcelis CM, Zwink N, Reutter H, van Rooij IA. Bias in patient series with VACTERL association. Am J Med Genet A. 2011;155A:2039–2041. [PubMed]
  • Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JM, Grange DK, Guttmacher AE, Hannibal MC, Henn W, Hennekam RC, Holmes LB, Hoyme HE, Leppig KA, Lin AE, Macleod P, Manchester DK, Marcelis C, Mazzanti L, McCann E, McDonald MT, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JA, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GC, Biesecker LG. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet. 2005;76:609–622. [PubMed]
  • Holden ST, Cox JJ, Kesterton I, Thomas NS, Carr C, Woods CG. Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome. J Med Genet. 2006;43:750–754. [PMC free article] [PubMed]
  • Källén K, Mastroiacovo P, Castilla EE, Robert E, Källén B. VATER non-random association of congenital malformations: study based on data from four malformation registers. Am J Med Genet. 2001;101:26–32. [PubMed]
  • Kang S, Graham JM, Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet. 1997;15:266–268. [PubMed]
  • Kantaputra PN, Mundlos S, Sripathomsawat W. A novel homozygous Arg222Trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Med Genet A. 2010;152A:2832–2837. [PubMed]
  • Kaufman RL, Hartmann AF, McAlister WH. Family studies in congenital heart disease, II: A syndrome of hydrometrocolpos, postaxial polydactyly and congenital heart disease. Birth Defects Orig Art Ser. 1972;8:85–87.
  • Khoury MJ, Cordero JF, Greenberg F, James LM, Erickson JD. A population study of the VACTERL association: evidence for its etiologic heterogeneity. Pediatrics. 1983;71:815–820. [PubMed]
  • Killoran CE, Abbott M, McKusick VA, Biesecker LG. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin Genet. 2000;58:28–30. [PubMed]
  • Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, Kirillova I, De Marco P, Merello E, Hayes JM, Wallingford JB, Drapeau P, Capra V, Gros P. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med. 2007;356:1432–1437. [PubMed]
  • Knijnenburg J, van Bever Y, Hulsman LO, van Kempen CA, Bolman GM, van Loon RL, Beverloo HB, vanZutven LJ. A 600 kb triplication in the cat eye syndrome critical region causes anorectal, renal and preauricular anomalies in a three-generation family. Eur J Hum Genet. 2012 [Epub ahead of print] [PMC free article] [PubMed]
  • Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–1452. [PubMed]
  • Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002;11:2979–2987. [PubMed]
  • Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy. J Med Genet. 2003;40:473–478. [PMC free article] [PubMed]
  • Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W. Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet. 1998;18:81–83. [PubMed]
  • Krantz ID, Piccoli DA, Spinner NB. Clinical and molecular genetics of Alagille syndrome. Curr Opin Pediatr. 1999;11:558–564. [PubMed]
  • Krantz ID, McCallum J, DeScipio C, Kaur M, Gillis LA, Yaeger D, Jukofsky L, Wasserman N, Bottani A, Morris CA, Nowaczyk MJ, Toriello H, Bamshad MJ, Carey JC, Rappaport E, Kawauchi S, Lander AD, Calof AL, Li HH, Devoto M, Jackson LG. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet. 2004;36:631–635. [PubMed]
  • Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16:243–251. [PubMed]
  • Li Y, Pawlik B, Elcioglu N, Aglan M, Kayserili H, Yigit G, Percin F, Goodman F, Nürnberg G, Cenani A, Urquhart J, Chung BD, Ismail S, Amr K, Aslanger AD, Becker C, Netzer C, Scambler P, Eyaid W, Hamamy H, Clayton-Smith J, Hennekam R, Nürnberg P, Herz J, Temtamy SA, Wollnik B. LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome. Am J Hum Genet. 2010;86:696–706. [PubMed]
  • Linden H, Williams R, King J, Blair E, Kini U. Ulnar Mammary syndrome and TBX3: expanding the phenotype. Am J Med Genet A. 2009;149A:2809–2812. [PubMed]
  • Lonardo F, Sabba G, Luquetti DV, Monica MD, Scarano G. Al-Awadi/Raas-Rothschild syndrome: two new cases and review. Am J Med Genet A. 2007;143A:3169–3174. [PubMed]
  • Marcelis CL, Hol FA, Graham GE, Rieu PN, Kellermayer R, Meijer RP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer AP. Genotype-phenotype correlations in MYCN-related Feingold syndrome. Hum Mutat. 2008;29:1125–1132. [PubMed]
  • Kamath BM, Podkameni G, Hutchinson AL, Leonard LD, Gerfen J, Krantz ID, Piccoli DA, Spinner NB, Loomes KM, Meyers K. Renal anomalies in Alagille syndrome: A disease-defining feature. Am J Med Genet A. 2012 [Epub ahead of print] [PubMed]
  • Kim J, Kim P, Hui CC. The VACTERL association: lessons from the Sonic hedgehog pathway. Clin Genet. 2001;59:306–315. [PubMed]
  • McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79:169–173. [PubMed]
  • McDermott DA, Bressan MC, He J, Lee JS, Aftimos S, Brueckner M, Gilbert F, Graham GE, Hannibal MC, Innis JW, Pierpont ME, Raas-Rothschild A, Shanske AL, Smith WE, Spencer RH, St John-Sutton MG, van Maldergem L, Waggoner DJ, Weber M, Basson CT. TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome. Pediatr Res. 2005;58:981–986. [PubMed]
  • McDonald-McGinn DM, Driscoll DA, Bason L, Christensen K, Lynch D, Sullivan K, Canning D, Zavod W, Quinn N, Rome J. Autosomal dominant “Opitz” GBBB syndrome due to a 22q11.2 deletion. Am J Med Genet. 1995;59:103–113. [PubMed]
  • McGregor L, Makela V, Darling SM, Vrontou S, Chalepakis G, Roberts C, Smart N, Rutland P, Prescott N, Hopkins J, Bentley E, Shaw A, Roberts E, Mueller R, Jadeja S, Philip N, Nelson J, Francannet C, Perez-Aytes A, Megarbane A, Kerr B, Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997;15:179–180. [PubMed]
  • Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764. [PubMed]
  • Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997;15:179–180. [PubMed]
  • Nora JJ, Nora AH. Birth defects and oral contraceptives. Lancet. 1973;1:941–942. [PubMed]
  • Nora AH, Nora JJ. A syndrome of multiple congenital anomalies associated with teratogenic exposure. Arch Environ Health. 1975;30:17–21. [PubMed]
  • Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16:235–242. [PubMed]
  • Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, Robu ME, Schleiffarth JR, Billington CJ, Jr, van Bokhoven H, Hoogeboom JM, Mazzeu JF, Petryk A, Schimmenti LA, Brunner HG, Ekker SC, Lohr JL. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239:327–337. [PubMed]
  • Pié J, Gil-Rodríguez MC, Ciero M, López-Viñas E, Ribate MP, Arnedo M, Deardorff MA, Puisac B, Legarreta J, de Karam JC, Rubio E, Bueno I, Baldellou A, Calvo MT, Casals N, Olivares JL, Losada A, Hegardt FG, Krantz ID, Gómez-Puertas P, Ramos FJ. Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome. Am J Med Genet A. 2010;152A:924–929. [PMC free article] [PubMed]
  • Powell CM, Michaelis RC. Townes-Brocks syndrome. J Med Genet. 1999;36:89–93. [PMC free article] [PubMed]
  • Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, Feldman GJ, Volta M, Andolfi G, Gilgenkrantz S, Marion RW, Hennekam RC, Opitz JM, Muenke M, Ropers HH, Ballabio A. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet. 1997;17:285–291. [PubMed]
  • Quan L, Smith DW. The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects. J Pediatr. 1973;82:104–107. [PubMed]
  • Rittler M, Paz JE, Castilla EE. VACTERL association, epidemiologic definition and delineation. Am J Med Genet. 1996;63:529–536. [PubMed]
  • Robinow M, Silverman FN, Smith HD. A newly recognized dwarfing syndrome. Am J Dis Child. 1969;117:645–651. [PubMed]
  • Rosias PR, Sijstermans JM, Theunissen PM, Pulles-Heintzberger CF, De Die-Smulders CE, Engelen JJ, Van Der Meer SB. Phenotypic variability of the cat eye syndrome. Case report and review of the literature. Genet Couns. 2001;12:273–282. [PubMed]
  • Ross AJ, Ruiz-Perez V, Wang Y, Hagan DM, Scherer S, Lynch SA, Lindsay S, Custard E, Belloni E, Wilson DI, Wadey R, Goodman F, Orstavik KH, Monclair T, Robson S, Reardon W, Burn J, Scambler P, Strachan T. A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet. 1998;20:358–361. [PubMed]
  • Schramm C, Draaken M, Bartels E, Boemers TM, Aretz S, Brockschmidt FF, Nöthen MM, Ludwig M, Reutter H. De novo microduplication at 22q11.21 in a patient with VACTERL association. Eur J Med Genet. 2011;54:9–13. [PubMed]
  • Selicorni A, Sforzini C, Milani D, Cagnoli G, Fossali E, Bianchetti MG. Anomalies of the kidney and urinary tract are common in de Lange syndrome. Am J Med Genet A. 2005;132:395–397. [PubMed]
  • Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24:101–122. [PMC free article] [PubMed]
  • Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH, II, Harris PC, Johnson CA. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. 2006;38:191–196. [PubMed]
  • Solomon BD. VACTERL/VATER Association. Orphanet J Rare Dis. 2011;6:56. [PMC free article] [PubMed]
  • Solomon BD, Patel A, Cheung SW, Pineda-Alvarez DE. VACTERL association and mitochondrial dysfunction. Birth Defects Res A Clin Mol Teratol. 2011a;91:192–194. [PMC free article] [PubMed]
  • Solomon BD, Pineda-Alvarez DE, Hadley DW, Keaton AA, Agochukwu NB, Raam MS, Carlson-Donohoe HE, Kamat A, Chandrasekharappa SC. De novo deletion of chromosome 20q13.33 in a patient with tracheo-esophageal fistula, cardiac defects and genitourinary anomalies implicates GTPBP5 as a candidate gene. Birth Defects Res A Clin Mol Teratol. 2011b;91:862–865. [PMC free article] [PubMed]
  • Solomon BD, Pineda-Alvarez DE, Raam MS, Bous SM, Keaton AA, Vélez JI, Cummings DA. Analysis of component findings in 79 patients diagnosed with VACTERL association. Am J Med Genet A. 2010a;152A:2236–2244. [PMC free article] [PubMed]
  • Solomon BD, Pineda-Alvarez DE, Raam MS, Cummings DA. Evidence for inheritance in patients with VACTERL association. Hum Genet. 2010b;127:731–733. [PMC free article] [PubMed]
  • Solomon BD, Raam MS, Pineda-Alvarez DE. Analysis of genitourinary anomalies in patients with VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association. Congenit Anom (Kyoto) 2011c;51:87–91. [PMC free article] [PubMed]
  • Sparrow DB, Chapman G, Smith AJ, Mattar MZ, Major JA, O’Reilly VC, Saga Y, Zackai EH, Dormans JP, Alman BA, McGregor L, Kageyama R, Kusumi K, Dunwoodie SL. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell. 2012;149:295–306. [PubMed]
  • Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, Ou Z, Wiszniewska J, Driscoll DJ, Maisenbacher MK, Bolivar J, Bauer M, Zackai EH, McDonald-McGinn D, Nowaczyk MM, Murray M, Hustead V, Mascotti K, Schultz R, Hallam L, McRae D, Nicholson AG, Newbury R, Durham-O’Donnell J, Knight G, Kini U, Shaikh TH, Martin V, Tyreman M, Simonic I, Willatt L, Paterson J, Mehta S, Rajan D, Fitzgerald T, Gribble S, Prigmore E, Patel A, Shaffer LG, Carter NP, Cheung SW, Langston C, Shaw-Smith C. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84:780–791. [PMC free article] [PubMed]
  • Stern AM, Gall JC, Jr, Perry BL, Stimson CW, Weitkamp LR, Poznanski AK. The hand-food-uterus syndrome: a new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic abnormalities, and partial duplication of the female genital tract. J Pediatr. 1970;77:109–116. [PubMed]
  • Temtamy SA, Miller JD. Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr. 1974;85:345–349. [PubMed]
  • Tonkin ET, Wang TJ, Lisgo S, Bamshad MJ, Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, ismutated in Cornelia de Lange syndrome. Nat Genet. 2004;36:636–41. [PubMed]
  • Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome) J Clin Invest. 2002;110:381–388. [PMC free article] [PubMed]
  • Tyreman M, Abbott KM, Willatt LR, Nash R, Lees C, Whittaker J, Simonic I. High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. J Med Genet. 2009;46:531–541. [PubMed]
  • Umaña LA, Magoulas P, Bi W, Bacino CA. A male newborn with VACTERL association and Fanconi anemia with a FANCB deletion detected by array comparative genomic hybridization (aCGH) Am J Med Genet A. 2011;155A:3071–3074. [PubMed]
  • Unger S, Böhm D, Kaiser FJ, Kaulfuss S, Borozdin W, Buiting K, Burfeind P, Böhm J, Barrionuevo F, Craig A, Borowski K, Keppler-Noreuil K, Schmitt-Mechelke T, Steiner B, Bartholdi D, Lemke J, Mortier G, Sandford R, Zabel B, Superti-Furga A, Kohlhase J. Mutations in the cyclin family member FAM58A cause an X-linked dominant disorder characterized by syndactyly, telecanthus and anogenital and renal malformations. Nat Genet. 2008;40:287–289. [PubMed]
  • Urioste M, del Garcia-Andrade MC, Valle L, Robledo M, González-Palacios F, Méndez R, Ferreirós J, Nuño J, Benítez J. Malignant degeneration of presacral teratoma in the Currarino anomaly. Am J Med Genet A. 2004;128A:299–304. [PubMed]
  • van Bokhoven H, Celli J, van Reeuwijk J, Rinne T, Glaudemans B, van Beusekom E, Rieu P, Newbury-Ecob RA, Chiang C, Brunner HG. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet. 2005;37:465–467. [PubMed]
  • van Haelst MM, Maiburg M, Baujat G, Jadeja S, Monti E, Bland E, Pearce K, Hennekam RC, Scambler PJ. Fraser Syndrome Collaboration Group. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet A. 2008;146A:2252–2257. [PubMed]
  • Van Maldergem L, Siitonen HA, Jalkh N, Chouery E, De Roy M, Delague V, Muenke M, Jabs EW, Cai J, Wang LL, Plon SE, Fourneau C, Kestilä M, Gillerot Y, Mégarbané A, Verloes A. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006;43:148–152. [PMC free article] [PubMed]
  • Vera-Roman JM. Robinow dwarfing syndrome accompanied by penile agenesis and hemivertebrae. Am J Dis Child. 1973;126:206–208. [PubMed]
  • Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36:955–957. [PubMed]
  • Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010;116:3715–3723. [PubMed]
  • Wainwright B, Woolf AS, Winter RM, Scambler PJ. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat Genet. 2003;34:203–208. [PubMed]
  • Walsh LE, Vance GH, Weaver DD. Distal 13q Deletion Syndrome and the VACTERL association: case report, literature review, and possible implications. Am J Med Genet. 2001;98:137–144. [PubMed]
  • Wang M, Clericuzio CL, Godfrey M. Familial occurrence of typical and severe lethal congenital contractural arachnodactyly caused by missplicing of exon 34 of fibrillin-2. Am J Hum Genet. 1996;59:1027–1034. [PubMed]
  • Wang RY, Jones JR, Chen S, Rogers RC, Friez MJ, Schwartz CE, Graham JM., Jr A previously unreported mutation in a Currarino syndrome kindred. Am J Med Genet A. 2006;140:1923–1930. [PubMed]
  • Wessels MW, Kuchinka B, Heydanus R, Smit BJ, Dooijes D, de Krijger RR, Lequin MH, de Jong EM, Husen M, Willems PJ, Casey B. Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? J Med Genet. 2010;47:351–355. [PubMed]
  • Weaver DD, Mapstone CL, Yu PL. The VATER association. Analysis of 46 patients. Am J Dis Child. 1986;140:225–229. [PubMed]
  • Wheeler PG, Weaver DD. Adults with VATER association: long-term prognosis. Am J Med Genet A. 2005;138A:212–217. [PubMed]
  • Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M, Turnpenny PD, Fantes JA, van Heyningen V, Fitzpatrick DR. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet. 2006;15:1413–1422. [PubMed]
  • Wollnik B, Kayserili H, Uyguner O, Tukel T, Yuksel-Apak M. Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family. Ann Genet. 2002;45:213–217. [PubMed]
  • Woods CG, Stricker S, Seemann P, Stern R, Cox J, Sherridan E, Roberts E, Springell K, Scott S, Karbani G, Sharif SM, Toomes C, Bond J, Kumar D, Al-Gazali L, Mundlos S. Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Hum Genet. 2006;79:402–408. [PubMed]
  • Zentner GE, Layman WS, Martin DM, Scacheri PC. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A. 2010;152A:674–686. [PMC free article] [PubMed]