Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

WT1 disorder is characterized by congenital/infantile or childhood onset of steroid-resistant nephrotic syndrome (SRNS), a progressive glomerulopathy that does not respond to standard steroid therapy. Additional common findings can include disorders of testicular development (with or without abnormalities of the external genitalia and/or müllerian structures) and Wilms tumor. Less common findings are congenital anomalies of the kidney and urinary tract (CAKUT) and gonadoblastoma. While various combinations of renal and other findings associated with a WT1 pathogenic variant were designated as certain syndromes in the past, those designations are now recognized to be part of a phenotypic continuum and are no longer clinically helpful.

Heterotaxy Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. Multiple Types of Congenital Heart Defects Congenital heart defects (CHTD) are among the most common congenital defects, occurring with an incidence of 8/1,000 live births. The etiology of CHTD is complex, with contributions from environmental exposure, chromosomal abnormalities, and gene defects. Some patients with CHTD also have cardiac arrhythmias, which may be due to the anatomic defect itself or to surgical interventions (summary by van de Meerakker et al., 2011). Reviews Obler et al. (2008) reviewed published cases of double-outlet right ventricle and discussed etiology and associations. Genetic Heterogeneity of Visceral Heterotaxy See also HTX2 (605376), caused by mutation in the CFC1 gene (605194) on chromosome 2q21; HTX3 (606325), which maps to chromosome 6q21; HTX4 (613751), caused by mutation in the ACVR2B gene (602730) on chromosome 3p22; HTX5 (270100), caused by mutation in the NODAL gene (601265) on chromosome 10q22; HTX6 (614779), caused by mutation in the CCDC11 gene (614759) on chromosome 18q21; HTX7 (616749), caused by mutation in the MMP21 gene (608416) on chromosome 10q26; HTX8 (617205), caused by mutation in the PKD1L1 gene (609721) on chromosome 7p12; HTX9 (618948), caused by mutation in the MNS1 gene (610766) on chromosome 15q21; HTX10 (619607), caused by mutation in the CFAP52 gene (609804) on chromosome 17p13; HTX11 (619608), caused by mutation in the CFAP45 gene (605152) on chromosome 1q23; and HTX12 (619702), caused by mutation in the CIROP gene (619703) on chromosome 14q11. Genetic Heterogeneity of Multiple Types of Congenital Heart Defects An X-linked form of CHTD, CHTD1, is caused by mutation in the ZIC3 gene on chromosome Xq26. CHTD2 (614980) is caused by mutation in the TAB2 gene (605101) on chromosome 6q25. A form of nonsyndromic congenital heart defects associated with cardiac rhythm and conduction disturbances (CHTD3; 614954) has been mapped to chromosome 9q31. CHTD4 (615779) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26. CHTD5 (617912) is caused by mutation in the GATA5 gene (611496) on chromosome 20q13. CHTD6 (613854) is caused by mutation in the GDF1 gene (602880) on chromosome 19p13. CHTD7 (618780) is caused by mutation in the FLT4 gene (136352) on chromosome 5q35. CHTD8 (619657) is caused by mutation in the SMAD2 gene (601366) on chromosome 18q21. CHTD9 (620294) is caused by mutation in the PLXND1 gene (604282) on chromosome 3q22.

Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder. For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Right atrial isomerism is characterized by bilateral triangular, morphologically right atrial, appendages, both joining the atrial chamber along a broad front with internal terminal crest.

Visceral heterotaxy-6 (HTX6) is characterized by dextrocardia with or without accompanying complex cardiovascular defects, as well as variable manifestations of visceral heterotaxy, including situs inversus totalis (Perles et al., 2012).

Autosomal visceral heterotaxy-7 is an autosomal recessive developmental disorder characterized by complex congenital heart malformations and/or situs inversus and caused by defects in the normal left-right asymmetric positioning of internal organs. The phenotype is variable (summary by Guimier et al., 2015). For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Cardioacrofacial dysplasia-2 (CAFD2) is characterized by congenital cardiac defects, primarily common atrium or atrioventricular septal defect; limb anomalies, including short limbs, brachydactyly, and postaxial polydactyly; and dysmorphic facial features. Developmental delay of variable severity has also been observed (Palencia-Campos et al., 2020). For a discussion of genetic heterogeneity of CAFD, see CAFD1 (619142).

Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).

Visceral heterotaxy-12 (HTX12) is an embryonic developmental disorder characterized by defects in the asymmetric positioning of visceral organs across the left-right axis, known as laterality defects. The phenotype is highly variable, ranging from complete organ reversal (situs inversus totalis) to selective misarrangement of organs (situs ambiguus) such as the liver, spleen, and pancreas. The disorder is often associated with dextrocardia or variable complex congenital heart defects. Early death may occur in the most severe cases (summary by Szenker-Ravi et al., 2022). For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Primary ciliary dyskinesia-53 (CILD53) is an autosomal recessive disorder characterized by randomization of the left-right body asymmetry and respiratory symptoms (Hjeij et al., 2023). For a discussion of genetic heterogeneity of primary ciliary dyskinesia, see CILD1 (244400).