Heterotaxy, Visceral, 7, Autosomal

A number sign (#) is used with this entry because of evidence that autosomal visceral heterotaxy-7 (HTX7) is caused by homozygous or compound heterozygous mutation in the MMP21 gene (608416) on chromosome 10q26.

Description

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).

Clinical Features

Perles et al. (2015) reported 3 sibs, born of consanguineous parents, with a congenital laterality disorder. One patient presented with cyanosis at age 3 months and was found to have dextrocardia with atrial situs inversus, complete atrioventricular canal defect, transposition of the great arteries (TGA) and pulmonary atresia with a duct-like aortopulmonary collateral. Her brother presented with severe cyanosis soon after birth and was found to have visceral and atrial situs inversus with bilateral superior vena cava, a complete atrioventricular canal defect, and transposition of the great vessels with pulmonary atresia. Both patients underwent Blalock-Taussig shunt palliation. The sister had limited physical activity at age 23 years, but the bother was capable of moderate exercise at age 10. The third sib was asymptomatic, but was found to have situs inversus totalis. None of the sibs had features of ciliary dyskinesia, such as recurrent lung infections, chronic sinusitis, otitis media or nasal polyps, or abnormal nasal nitric oxide.

Guimier et al. (2015) reported 14 patients from 9 unrelated families with visceral heterotaxy. Almost all patients had complex cardiac anomalies, variably including dextrocardia, transposition of the great arteries, atrial and/or ventricular septal defects, abnormal vessel draining, interruption of the vena cava drainage, and anomalous pulmonary venous return. At least 1 patient did not have cardiac defects, but did have situs inversus totalis. Extracardiac laterality defects were also common but variable, and included situs inversus totalis, situs ambiguus, pulmonary isomerism, intestinal malrotation, midline liver, and polysplenia. One mutation carrier was reportedly unaffected.

Akawi et al. (2015) reported 3 patients from 2 unrelated families with HTX7. In the first family, a boy had dextrocardia, ventricular and atrial septal defects, interrupted inferior vena cava, and interrupted aortic arch. A deceased sib (fetus) had right-sided stomach, total anomalous pulmonary return, mitral atresia, and double-outlet right ventricle. The only affected individual in the second family had multiple cardiac malformations, transposition of the great arteries, and global developmental delay with dysmorphic features.

Inheritance

The transmission pattern of HTX7 in the families reported by Guimier et al. (2015) was consistent with autosomal recessive inheritance. One family showed some evidence of incomplete penetrance.

Molecular Genetics

In 3 sibs, born of consanguineous Arab parents, with HTX7, Perles et al. (2015) identified a homozygous truncating mutation in the MMP21 gene (608416.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies in zebrafish (see ANIMAL MODEL) suggested that the mutation affected NOTCH1 (190198) signaling during development.

In affected members of 9 unrelated families with HTX7, Guimier et al. (2015) identified homozygous or compound heterozygous mutations in the MMP21 gene (see, e.g., 608416.0002-608416.0008). Mutations in the first 2 families were found by whole-exome or whole-genome sequencing; mutations in subsequent families were found by targeted sequencing of the MMP21 gene in 264 probands with heterotaxy and/or cardiac laterality defects. Functional studies of the variants were not performed, but expression of 1 of the missense mutations in mice resulted in an increased frequency of complex congenital heart defects and heterotaxy, suggesting a loss of function.

In 3 affected individuals from 2 unrelated families with HTX7, Akawi et al. (2015) identified compound heterozygous mutations in the MMP21 gene (608416.0009-608416.0012). The mutations, which were found by exome sequencing, segregated with the disorder in the families; functional studies were not performed. The patients were part of a large study of 4,125 families with a variety of severe developmental disorders who underwent exome analysis.

Animal Model

Akawi et al. (2015) reported that 2 heterotaxy mouse models, 'Miri' and 'Koli,' that were identified from a phenotype-based ENU mutagenesis screen carried pathogenic Mmp21 missense mutations (W177L and Y325N) affecting the zinc-binding domain. The mutant mice showed visceral heterotaxy with laterality heart defects commonly associated with heterotaxy. Features included dextrocardia, transposition of the great arteries, atrial and ventricular defects, abnormal vessel drainage, lung isomerism, inverted liver lobation, and dextrogastria. Videomicroscopy of the embryonic node showed normal cilia motility, suggesting that Mmp21 acts downstream of motile cilia.

By whole-exome sequencing in a large study of chemically mutagenized mice with various forms of congenital heart disease, Li et al. (2015) identified 91 recessive mutations in 61 genes, including the extracellular matrix-related gene Mmp21. Mice with Mmp21 mutations had congenital heart disease with laterality defects.

Perles et al. (2015) found that morpholino knockdown of the mmp21 ortholog in zebrafish resulted in a dose-dependent induction of positional heart-looping defects. Mutant embryos also showed abnormal expression pattern of the left-identity marker 'southpaw' (spaw), suggesting that the heart-looping defect is associated with abnormal left-right patterning. Mutant embryos also showed upregulation of NOTCH1 target genes. Normal embryos showed mmp21 expression close to and rostral to Kupffer vesicle prior to establishment of left-right asymmetry.

Guimier et al. (2015) found that expression of mmp21 in zebrafish embryos was restricted to Kupffer vesicle, and morpholino knockdown resulted in randomized heart looping. Introduction of the human missense mutation I226T (608416.0002) into mice resulted in an increased frequency of complex congenital heart defects, situs inversus, and heterotaxy compared to controls.