Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family

Abstract

FG syndrome (FGS, MIM 305450) is a rare X-linked recessive disorder comprising mental retardation and multiple malformations. Various families have been described to date, increasing our knowledge of the phenotype variability and making the clinical diagnosis complex, especially in sporadic patients. The first locus for FG syndrome (FGS1) was linked to chromosome region Xq12-q21.31, but other families have been excluded from this locus. The genetic heterogeneity of FG syndrome has been confirmed by analysis of an X chromosome inversion [inv(X)(q11q28)] in an affected boy and in his mentally retarded maternal uncle, suggesting that an additional locus for FG syndrome (FGS2, MIM 300321) is located at either Xq11 or Xq28. Recently, a third locus (FGS3) has been mapped to Xp22.3. We have identified and clinically characterized an Italian FG family, including 31 members with three affected males in two generations and two obligate carriers. We have excluded linkage to known FGS loci, whereas an extensive study of the whole X chromosome has yielded a maximum LOD score (Z max ) of 2.66 (recombination fraction=0) for markers between DXS8113 and sWXD805. This new locus for FG syndrome corresponds to a region of approximately 4.6 Mb on the X chromosome.

A de novo splice site mutation in CASK causes FG syndrome‐4 and congenital nystagmus

“…One patient with a milder mutation has been diagnosed with the FG4‐syndrome previously [Burglen et al, ]. Notably, this latter patient also a partial splicing defect due to a partial skipping of the exon two of CASK with the expression of multiple transcripts [Piluso et al, , ]. This is similar to our case, demonstrating a possible genotype–phenotype correlation.…”

“…The FG syndrome‐4 phenotype has so far been linked specifically to an amine‐terminus domain mutation of the CASK gene that resulted in a partial skipping of exon two and the production of an abnormal out‐of‐frame transcript along with the wild‐type RNA [Piluso et al, , ]. The hypomorphic mutation we have presented in this paper is in the C‐terminal region of the protein and results in general characteristics of FG syndrome, including congenital hypotonia, feeding difficulties, severe constipation, distinctive minor facial anomalies, and a generally talkative and affable personality [Opitz and Kaveggia, ; Graham et al, ; Burglen et al, ].…”

Natural history of Christianson syndrome

“…The Angelman syndrome-like demeanor noted with SLC9A6 mutations has not been noted with CASK mutations [Anna Hackett, personal communication, 2009]. Piluso et al [2003, 2009] described a missense mutation of CASK in 3 males in a family with normal OFC, hypertelorism, frontal hair upsweep, constipation, hypotonia, aggressive behavior, and epilepsy. There was no report of ocular or cerebellar findings or signs of Angelman-like demeanor.…”

Calcium/calmodulin‐dependent serine protein kinase and mental retardation

“…In 2002, the chromosomal region Xp11.4‐p11.23 was reported to contain the locus of nonspecific XLMR (MRX78) 32. Later, one of the loci of FG syndrome (FGS, MIM 305450), namely, FGS4, was mapped to Xp11.4‐11.3 33. FGS is a rare X‐linked recessive disorder comprising mental retardation and multiple congenital anomalies.…”

“…Although the reports that Najm and colleagues28 and Piluso and coauthors33 contributed describe the XLMR in their patients as caused by mutations in the CASK gene, there is a major disagreement between their studies. In Najm and colleagues'28 study, all five patients are characterized by microcephaly.…”