Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia

Periventricular heterotopia (PH) is a malformation of cortical development characterized by the ectopic localization of neuronal nodules along the lateral ventricle. Mutations in X-linked filamin A gene are the most common cause of PH, although a rarer autosomal recessive form of PH with microcephaly due to ARFGEF2 mutations has been described [Sheen et al., 2001]. Affected individuals generally are of normal intelligence and most often present with adolescent onset seizures. The 1p36 deletion syndrome is associated with multiple congenital anomalies caused by haploinsufficiency of numerous contiguous genes. This deletion produces specific physical characteristics such as distinctive facial anomalies (pointed chin, flat nose, low set ears) and cardiovascular malformations (atrial septal defect, patent ductus arteriosus, tetralogy of Fallot). Central nervous system (CNS) defects include mental retardation, cranial nerve abnormalities (VI nerve palsies, optic disc anomalies, sensorineural hearing loss), neonatal hypotonia, cortical dysplasia, and seizures [Heilstedt et al., 2003; Kurosawa et al., 2005; Battaglia, 2005]. A reduction in the KCNAB2 potassium channel betasubunit has been hypothesized to be responsible for the seizures [Hirose et al., 2002]. Affected individuals can display outbursts, tendencies to strike people, and self-injurious behavior, as well as autistic-like behaviors [Slavotinek et al., 1999]. Previous neuroimaging and postmortem studies on individuals with 1p36 deletions have revealed mild CNS structural abnormalities. Deletions involving the most distal p-terminus (D1S508, 1p36.23-> 1pter) have only been associated with microcephaly, mild ventricular asymmetry, and ventricular enlargement [Kurosawa et al., 2005; Slavotinek et al., 1999]. An interstitial deletion (1p36.1->1p36.2) was suggested as causal for the development of neuroblastoma in a single case report [Keppler-Noreuil et al., 1995]. Finally, a series of three patients harboring 1p36.22->1pter deletions was reported to have hydrocephalus by cranial ultrasound but no mention of PH [Keppler-Noreuil et al., 1995]. To date, there have been no reported associations of PH with chromosome 1p36 deletions. Here, we describe the first case describing PH in an individual with a 1p36.22-> 1pter deletion. This study was approved by the IRB at the respective institutions in accordance with NIH. Informed consent was obtained from the participating subject’s parents. Genomic DNA was extracted from peripheral whole blood lymphocytes using standard blood DNA isolation techniques (Qiagen Inc., Valencia, CA). Metaphase chromosome analysis of lymphocytes was performed according to standard protocols. Initial routine karyotyping on the child was read as normal, although deletions on 1p36 are commonly missed due to the Giemsa-negative/poor staining in this region. Given the numerous clinical features seen in this subject, FISH analysis utilizing 41 subtelomere probes was performed (Genzyme laboratories (Hawthorne, NY), using Vysis probes (Downers Grove, IL). Results were confirmed with a chromosome 1p subtelomere probe (1pSUBTEL; Vysis) and the D1Z2 midi-satellite probe with repeats in band 1p36 (Oncor). The D1Z2 probe is used for confirmationof a commondeletion interval (1p36.3). A chromosome 1 centromere probe (D1Z5; Vysis)