X-linked mental retardation (XLMR) entities are estimated to have at least a prevalence of 1.8 of 1,000 males with a carrier prevalence of 2.4 in 1,000 [Glass, 1991]. Of this group of genetic conditions, the fragile X syndrome accounts for less than 40% of the cases [Opitz, 1986]. Thus, as a whole, XLMR constitutes the most frequent cause of mental retardation in males. One XLMR condition is the Carpenter-Waziri syndrome (CWS), an X-linked recessive condition first reported in 1988 [Carpenter et al., 1988] and originally referred to as Carpenter syndrome [Neri et al., 1991]. Affected males had moderate mental retardation and were in a trainable setting. Clinically, these males had a “coarse” facial appearance (bushy eyebrows; broad, depressed nasal bridge with wide nasal tip; prominent lower lip; widely spaced teeth), short stature (5th centile in three affected males and 20th centile in the fourth), variable head circumference ranging from 5th to 20th centile, variable weight ranging from 5th to 50th centile, brachydactyly with excessive skin creases, and widening of the knuckles. Recently the gene was mapped to the Xp11. 3-q23 with a maximum LOD score of 2.53 obtained at several loci [Carpenter et al., 1998]. In the proximal long arm region of the X chromosome there are two candidate genes for syndromal XLMR. One of these, ATP7A, is involved in the Menkes syndrome [Chelly et al., 1993]. This gene is not a likely candidate as the phenotypes for CWS and Menkes do not overlap. Mutations in the second gene, XNP (X-linked nuclear protein) have been found in patients with-thalassemia, X-linked mental retardation,(ATR-X, MIM# 301040)[Gibbons et al., 1995; Villard et al., 1996c]. These patients are characterized by severe mental retardation, HbH (4) inclusion bodies, genital abnormalities, and microcephaly [Gibbons et al., 1992], which are not present in CWS, whereas both ATR-X and CWS share some manifestations such as a depressed nasal bridge and a prominent lower lip [Carpenter et al., 1988, 1998; Gibbons et al., 1992]. Because of the overlap in localization and some of the clinical findings as mentioned above, we examined the patients with Carpenter-Waziri syndrome for mutations in the XNP gene. Here we report a missense mutation (I2052T) in the region of the helicase IV domain. This finding suggests that CWS and ATR-X are allelic conditions, thereby increasing the phenotypes known to be caused by XNP mutations.

Single strand conformational polymorphism (SSCP) analysis of exon 27 detected an altered pattern in the propositus. Subsequent sequence analysis demonstrated a T to C transition (T6356C), resulting in the substitution of a threonine residue for a isoleucine residue (I2052T). This mutation failed to either create or eliminate a restriction endonuclease site. Thus, a MboI site was created in the normal sequence using a modified primer [Haliassos et al., 1989]. The lack of the MboI site segregated with CWS in the family (Fig. 1) and the MboI site was found in 105 unrelated normal X chromosomes, thereby ruling out a rare polymorphic event.