Multigenerational autosomal dominant inheritance of 5p chromosomal deletions.

Am J Med Genet A 2016 Mar 24;170(3):583-93. Epub 2015 Nov 24.

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri.

Deletion of the short arm of chromosome 5 (5p-) is associated with phenotypic features including a cat-like cry in infancy, dysmorphic facial features, microcephaly, and intellectual disability, and when encompassing a minimal critical region, may be defined as Cri-du-Chat syndrome (CdCS). Most 5p deletions are de novo in origin, and familial cases are often associated with translocation and inversion. Herein, we report three multigenerational families carrying 5p terminal deletions of different size transmitted in an autosomal dominant manner causing variable clinical findings. Terminal 5p deletions and the mode of inheritance were clinically characterized and molecularly analyzed by a combination of microarray and fluorescence in situ hybridization analyses. Shared phenotypic features documented in this cohort included neuropsychiatric findings, poor growth, and dysmorphic facial features. This study supports newly recognized effects of aberrant SEMA5A and CTNND2 dosage on severity of autistic and cognitive phenotypes. Comparative analysis of the breakpoints narrows the critical region for the cat-like cry down to an interval less than 1 Mb encompassing a candidate gene ICE1, which regulates small nuclear RNA transcription. This study also indicates that familial terminal 5p deletion is a rare presentation displaying intra- and inter-familial phenotypic variability, the latter of which may be attributed to size and gene content of the deletion. The observed intra-familial phenotypic heterogeneity suggests that additional modifying elements including genetic and environmental factors may have an impact on the clinical manifestations observed in 5p deletion carriers, and in time, further high resolution studies of 5p deletion breakpoints will continue to aid in defining genotype-phenotype correlations.

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37445DOI Listing
March 2016
44 Reads

Publication Analysis

Top Keywords

dysmorphic facial
8
terminal deletions
8
facial features
8
phenotypic features
8
cat-like cry
8
critical region
8
autosomal dominant
8
deletion
5
cohort included
4
included neuropsychiatric
4
additional modifying
4
suggests additional
4
analyses shared
4
documented cohort
4
shared phenotypic
4
features documented
4
findings poor
4
study supports
4
phenotypic heterogeneity
4
supports newly
4

References

(Supplied by CrossRef)
Cri du Chat syndrome
Cerruti et al.
Orphanet J Rare Dis 2006
Molecular definition of deletions of different segments of distal 5p that result in distinct phenotypic features
Church et al.
Am J Hum Genet 1995
A neuropsychological-genetic profile of atypical Cri du Chat syndrome: Implications for prognosis
Cornish et al.
J Med Genet 1999
Evidence for a distinct region causing a cat-like cry in patients with 5p deletions
Gersh et al.
Am J Hum Genet 1995
Familial 5p- syndrome
Kushnick et al.
Clin Genet 1984

Similar Publications