Feingold Syndrome 2

A number sign (#) is used with this entry because of evidence that Feingold syndrome-2 (FGLDS2) is caused by hemizygous deletion of the MIR17HG gene (609415) on chromosome 13q31.

Description

Feingold syndrome is an autosomal dominant disorder characterized by variable combinations of microcephaly, limb malformations, esophageal and duodenal atresias, and learning disability/mental retardation. Hand and foot abnormalities may include hypoplastic thumbs, clinodactyly of second and fifth fingers, syndactyly (characteristically between second and third and fourth and fifth toes), and shortened or absent middle phalanges. Cardiac and renal malformations, vertebral anomalies, and deafness have also been described in a minority of patients (summary by Teszas et al., 2006).

For a discussion of genetic heterogeneity of Feingold syndrome, see FGLDS1 (164280).

Clinical Features

De Pontual et al. (2011) studied 2 female probands with skeletal abnormalities consistent with a diagnosis of Feingold syndrome: microcephaly, short stature, and digital abnormalities including brachydactyly, brachymesophalangy of the second and fifth fingers, hypoplastic thumbs of variable severity, and cutaneous syndactyly of the toes. Both probands had mild mental retardation. Their fathers were similarly affected, and 1 of the probands had an affected sister.

Molecular Genetics

De Pontual et al. (2011) performed high-resolution CGH arrays in 10 probands with skeletal abnormalities consistent with a diagnosis of Feingold syndrome (see 164280) but who lacked any mutation at the MYCN gene (164840), and in 2 of the probands they identified germline hemizygous microdeletions at chromosome 13q31.3 that segregated with disease in both families. The deletion in the first patient spanned 2.89 Mb and encompassed 3 genes, LOC144776, MIR17HG (609415), and GPC5 (602446), whereas the deletion in the second patient spanned 165 kb and encompassed only MIR17HG and the first exon of GPC5. By searching the DECIPHER database (Firth et al., 2009), which contained array CGH data from more than 6,000 individuals with a variety of disorders, they identified a third proband who had a 180-kb hemizygous 13q31.3 microdeletion encompassing the entire MIR17HG gene and the first exon of GPC5. The third patient was not classified as having Feingold syndrome, but displayed a combination of features compatible with the diagnosis. Quantitative RT-PCR on total RNA of white blood cells from the 3 deletion-positive probands showed that expression of all 6 miRNAs encoded by MIR17HG was approximately 50% relative to that of controls. De Pontual et al. (2011) noted that whereas some predicted loss-of-function variants in GPC5 were listed in databases of genomes of healthy individuals, they identified no structural variants or polymorphisms directly affecting the miRNAs encoded by the miR17-92 cluster in those databases. In addition, mice harboring targeted deletion of the Mir17-92 cluster displayed a phenocopy of several key features of the human syndrome (see ANIMAL MODEL). De Pontual et al. (2011) stated that this was the first example of a miRNA gene responsible for a syndromic developmental defect in humans. The authors noted that none of the 3 individuals with a MIR17HG deletion had gastrointestinal atresia, leaving open the question of whether they represented true cases of Feingold syndrome or a new form of brachydactyly with short stature and microcephaly.

Animal Model

De Pontual et al. (2011) generated mice with a targeted deletion of a single Mir17-92 allele, which were viable and fertile, but significantly smaller than wildtype controls. Skeletal analysis of limbs from age- and sex-matched wildtype and mutant adult mice revealed a striking shortening of the mesophalanx of the fifth finger in heterozygous animals. Other long bones in the hands of mutant mice were only marginally shorter than in wildtype mice, and syndactyly was not observed in any of the hemizygous mice. Analysis of the skulls of mutant mice revealed shortening of the anterior-posterior axis and an overall reduction in size, consistent with microcephaly. In addition, targeted deletion of Mir17-92 did not negatively affect the expression of Gpc5 in the forelimbs of developing mouse embryos or in mouse embryo fibroblasts, showing that Mir17-92, but not Gpc5, is responsible for the key features observed in hemizygous mice.