Paul Bossuyt

Familial Mental Retardation Syndrome ATR-16 Due to an Inherited Cryptic Subtelomeric Translocation, t(3;16)(q29;p13.3)

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.

Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion

Wauters JG, Bossuyt PJ, Roelen L, van Roy B, Dumon J. Application of fluorescence in situ hybridization for early prenatal diagnosis of partial trisomy 6p/monosomy 6q due to a familial pericentric inversion. Clin Genet 1993: 44: 262–269.

Incidence of low-fluorescence α satellite region on chromosome 21 escaping detection of aneuploidy at interphase by FISH

Aneuploidy detection for chromosome 21 by fluorescence in situ hybridization (FISH) to interphase nuclei using a probe specific for the alphoid DNA sequences D21Z1/D13Z1 should be avoided. An extreme heteromorphism, resulting in misdiagnosis if interphase FISH is the only test employed, may be far more frequent (4/101) than expected.

Subregional mapping of the human lymphocyte prolyl oligopeptidase gene (PREP) to human chromosome 6q22

Prolyl oligopeptidase is a large monomeric proline specific serine endopeptidase, the activity of which correlates well with different stages of depression. We have subregionally mapped human lymphocytic prolyl oligopeptidase (PREP) by FISH using a cosmid probe. The probe mapped to the long arm of chromosome 6, and the signal clustered in band q22.

Regional mapping of a liver α-subunit gene of phosphorylase kinase (PHKA) to the distal region of human chromosome Xp

X-linked liver glycogenosis (XLG) is a glycogen storage disorder resulting from deficient activity of phosphorylase kinase (PHK). PHK consists of four different subunits: alpha, beta, gamma, and delta. Several genes encoding PHK subunits have been cloned and localized, but only the muscle alpha-subunit (PHKA) gene has been assigned to the X chromosome, in the region Xq12----q13. However, we have previously excluded the muscle PHKA gene as a candidate gene for the XLG mutation, as linkage analysis indicated that the mutation responsible for XLG is located in Xp22 and not in Xq12----q13. We report here the chromosomal localization by in situ hybridization of a liver PHKA gene to the distal region of chromosome Xp. Strong hybridization signals were observed on the distal part of the short arm of a chromosome identified as the X chromosome by cohybridization with an X chromosome-specific centromeric probe. The localization of this gene in the same chromosomal region as the disease gene responsible for XLG suggests that the liver PHKA gene is a highly likely candidate gene for the XLG mutation.

Assignment1 of the mouse Extl1 gene to the distal part of chromosome 4 by in situ hybridization and radiation hybrid mapping

Recently, a family of homologous genes was identified, comprising EXT1 on 8q23→q24 (Ahn et al., 1995) and EXT2 on 11p12→p11 (Wuyts et al., 1996), both causing multiple exostoses, and three EXT-like genes (EXTL1–3) mapped on 1p36.1 (Wise et al., 1997), 1p12→p11 (Wuyts et al., 1997) and 8p22→ p12 (Van Hul et al., 1998) respectively. Functional studies have revealed that the EXT genes (Lind et al., 1998) and EXTL2 (Kitagawa et al., 1999) are involved in heparan sulfate biosynthesis, while EXTL3 is thought to encode a receptor for Regproteins (Kobayashi et al., 2000). However, the function of EXTL1 still remains to be elucidated. Here, we describe the mapping of the mouse Extl1 gene to the distal part of mouse chromosome 4.