Diaphragmatic Hernia 3
A number sign (#) is used with this entry because of evidence that diaphragmatic hernia-3 (DIH3) is caused by heterozygous mutation in the ZFPM2 gene (603693) on chromosome 8q23.
For a general phenotypic description and a discussion of genetic heterogeneity of congenital diaphragmatic hernia, see (142340).
Clinical FeaturesTemple et al. (1994) reported 2 unrelated girls with isolated unilateral congenital diaphragmatic hernia. One child had a left posterolateral diaphragmatic hernia and a balanced reciprocal translocation (8;13)(q22.3;q22) inherited from her unaffected mother. The second child had a right posterolateral diaphragmatic hernia and a de novo balanced reciprocal translocation (8;15)(q22.3;q15). Temple et al. (1994) suggested that 8q22.3 may harbor a gene involved in isolated congenital diaphragmatic hernia.
Longoni et al. (2015) reported 13 patients with DIH3 associated with mutations in the ZFPM2 gene. All had isolated posterolateral congenital diaphragmatic hernia except 1 who also had craniofacial abnormalities, tetralogy of Fallot with an overriding aorta, a ventricular septal defect, and a narrow right ventricular outflow tract. The patient with additional features also had a 250-kb copy number gain of unknown significance on 8q24.21.
InheritanceThe transmission pattern of DIH3 in the families reported by Longoni et al. (2015) was consistent with autosomal dominant inheritance, with incomplete penetrance estimated at 37.5%.
CytogeneticsWat et al. (2011) identified 3 unrelated patients with congenital diaphragmatic hernia who had a heterozygous deletion of chromosome 8q involving the ZFPM2 gene, also known as FOG2. One patient had a 1.04-Mb deletion inherited from his unaffected father, and another had a 711-kb deletion also involving the OXR1 gene (605609) inherited from his unaffected mother. The third patient had a large 32.3-Mb deletion that also included the EXT1 (608177) and TRPS1 (604386) genes that are associated with Langer-Giedion syndrome (TRPS2; 150230); this infant had short extremities and died shortly after delivery. These patients were ascertained from a cohort of 45 patients with congenital diaphragmatic hernia.
Molecular GeneticsIn a deceased child with diaphragmatic development defects and severe primary pulmonary hypoplasia (see 265430), Ackerman et al. (2005) identified a de novo heterozygous mutation in the ZFPM2 gene (603693.0003). Postmortem analysis showed incomplete lung fissures bilaterally and a deep posterior left diaphragmatic eventration. The heart was grossly normal. Ackerman et al. (2005) suggested that mutations in the ZFPM2 gene may result in primary pulmonary and diaphragmatic defects.
In 2 of 96 patients with congenital diaphragmatic hernia, Bleyl et al. (2007) identified heterozygosity for novel sequence alterations in exon 7 of the ZFPM2 gene (603693.0004-603693.0005). Due to the lack of parental DNA, Bleyl et al. (2007) were unable to determine whether the changes were de novo.
Longoni et al. (2015) identified potentially pathogenic heterozygous variants in the ZFPM2 gene (see, e.g., 603693.0002) in 13 (5%) of 275 patients with congenital diaphragmatic hernia. Most of the mutations were missense, but 2 were truncating. In addition, 2 multiplex families of European origin with DIH were found to carry either a heterozygous deletion or a truncating mutation in the ZFPM2 gene, respectively. Functional studies were not performed.