Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: Possible digenic inheritance of a neural tube defect

Abstract

From a spina bifida clinic we have identified two patients with a syndrome of myelomeningocele and Waardenburg syndrome type 3 (WS3). The patients each possess a single, de novo, interstitial deletion of chromosome 2 (2q35-36.2), including the PAX3 gene. Deletion of PAX3 was confirmed by fluorescence in situ hybridization (FISH). Analysis with PAX3 and flanking microsatellites shows that the deleted interval of chromosome 2 is of paternal origin and is at least 2 and 6 cM in the two patients. Interstitial deletions in this region result in the Waardenburg syndrome (WS1), but have not been associated with neural tube defects (NTDs). Although other etiologies have not been formally excluded, these patients raise the possibility of a digenic etiology of their NTDs via a genetic interaction of the deleted PAX3 gene with a second unidentified locus.

Etiology, pathogenesis and prevention of neural tube defects

“…Meckel-Gruber syndrome, which is a rare autosomal recessive disorder, has an encephalocele component in addition to several severe CNS malformations (Ahdab-Barmada & Claassen 1990). Patients with interstitial deletion of chromosome 2 (2q35-36.2), including the PAX3 gene (Waardenburg syndrometype 3), are reported to have myelomeningocele (Nye et al 1998). Waardenburg syndrome (WS) is a pleiotropic, autosomal dominant condition with variable penetrance and expressivity.…”

Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome

“…Our WS‐III patient did not show evidence for a neural tube defect. In contrast, a heterozygous frameshift‐mutation in the PAX3 gene was described in a girl with spina bifida and mild signs of WS‐I and further a patient reported with myelomeningocele and WS‐III carrying an interstitial deletion of 2q35 including the PAX3 gene [Hol et al, 1995; Nye et al, 1998]. Heterozygous missense mutations and deletions in PAX3 have been also associated with familial and sporadic forms of WS‐III [Sheffer and Zlotogora, 1992; Tassabehji et al, 1995; Zlotogora et al, 1995; Read and Newton, 1997; Tekin et al, 2001].…”

Non‐multifactorial neural tube defects

“…Various deletions and ring chromosomes (Tables III–IV) have also been described in association with differing NTDs [Mita et al, 1980; Al‐Awadi et al, 1986; Jokiaho et al, 1989; Melnyk and Muraskas, 1993; Schinzel, 1994; Chinen et al, 1996; Dowton et al, 1997; Nye et al, 1998; Lukusa et al, 2001]. Chromosome regions discussed in the section on duplications will not be rediscussed here.…”

“… References: Mita et al [1980]; Telfer et al [1980]; Al‐Awadi et al [1986]; Rudelli [1987]; Jokiaho et al [1989]; Bogart et al [1990]; Melnyk and Muraskas [1993]; Morichon‐Delvallez et al [1993]; Plaja et al [1994]; Chen et al [1996]; Chinen et al [1996]; Nickel and Magenis [1996]; Dowton et al [1997]; Nye et al [1998]; Kennedy et al [2000]; Luo et al [2000]; Lukusa et al [2001]; Rodriguez et al [2002]. …”

“…As in duplications, NTDs are generally not common manifestations of most of these deletions, so again it is not clear what the significance is, although here again digenic interaction may be important. For example, Nye et al [1998] described two infants with NTD and Waardenburg syndrome type 3, who both had deletions of 2q35‐36.2. However, since it appears that most individuals with this deletion do not have NTD, a digenic etiology was postulated.…”