Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions.
Monosomy 1p36 is the most common terminal deletion syndrome seen in humans, occurring in approximately 1 in 5,000 live births. Common features include mental retardation, characteristic dysmorphic features, hypotonia, seizures, hearing loss, heart defects, cardiomyopathy, and behavior abnormalities. Similar phenotypes are seen among patients with a variety of deletion sizes, including terminal and interstitial deletions, complex rearrangements, and unbalanced translocations. Consequently, critical regions harboring causative genes for each of these features have been difficult to identify. Here we report on five individuals with 200-823 kb overlapping deletions of proximal 1p36.33, four of which are apparently de novo. They present with features of monosomy 1p36, including developmental delay and mental retardation, dysmorphic features, hypotonia, behavioral abnormalities including hyperphagia, and seizures. The smallest region of deletion overlap is 174 kb and contains five genes; these genes are likely candidates for some of the phenotypic features in monosomy 1p36. Other genes deleted in a subset of the patients likely play a contributory role in the phenotypes, including GABRD and seizures, PRKCZ and neurologic features, and SKI and dysmorphic and neurologic features. Characterization of small deletions is important for narrowing critical intervals and for the identification of causative or candidate genes for features of monosomy 1p36 syndrome.
Rosenfeld
Jill A
JA
Signature Genomic Laboratories, Spokane, Washington, USA.
Crolla
John A
JA
Tomkins
Susan
S
Bader
Patricia
P
Morrow
Bernice
B
Gorski
Jerome
J
Troxell
Robin
R
Forster-Gibson
Cynthia
C
Cilliers
Deirdre
D
Hislop
R Gordon
RG
Lamb
Allen
A
Torchia
Beth
B
Ballif
Blake C
BC
Shaffer
Lisa G
LG
D000015:Abnormalities, Multiple; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009006:Monosomy; D009422:Nervous System Diseases / Q000235:genetics; D010641:Phenotype; D011493:Protein Kinase C / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics; D012640:Seizures / Q000235:genetics; D013577:Syndrome; D055815:Young Adult; D000099221:Protein Kinase C zeta
D004268:DNA-Binding Proteins; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D011963:Receptors, GABA-A; D000099221:Protein Kinase C zeta; C464500:GABRD protein, human; C060614:SKI protein, human