A three-generation family with terminal microdeletion involving 5p15.33–32 due to a whole-arm 5;15 chromosomal translocation with a steady phenotype of atypical cri du chat syndrome

Elmakky, Amira; Carli, Diana; Lugli, Licia; Torelli, Paola; Guidi, Battista; Falcinelli, Cristina; Fini, Sergio; Ferrari, Fabrizio

doi:10.1016/j.ejmg.2014.02.005

Cited by 33 publications

(37 citation statements)

References 12 publications

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“…[13][14][15][16]25,26 To highlight the rapidly growing aetiological knowledge in this field, and the presence of significant neurodevelopmental comorbidity for many cases with CAS, we will illustrate genotypephenotype associations for a handful of single-gene variant and copy number-variant conditions associated with CAS ( Table 2). It was beyond the scope of this article to provide an exhaustive summary of all neurogenetic syndromes, copy number-variant conditions or even chromosomal rearrangements associated with CAS; however, CAS has been associated with conditions such as Floating-Harbor syndrome, 27 Cri du chat syndrome, 28 galactosaemia, 29 6q25.3 deletion, 16 7q11.23 duplication 26 and chromosomal translocations. 30,31 Moreover, we have not covered recently identified genes for CAS, where replication or further Inability to consistently produce a perceptually acceptable form of one or more speech sounds, in isolation or in words (e.g.…”

Section: Genetic Bases Of Casmentioning

confidence: 99%

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

Morgan

Webster

2018

J Paediatrics Child Health

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Childhood apraxia of speech (CAS) is a rare disorder of childhood that can leave a watermark of the impacts throughout the lifetime. Since being first described in the 1950s, aetiological insights have been limited. At a neurobiological level, clinical MRI scans fail to reveal overt neural anomalies in individual cases with CAS, although quantitative MRI methods have revealed subtle brain anomalies at a group level. Dramatic insights, however, occurred in the past decade from the discovery of genetic pathways underlying the phenotype. Several single genes and copy number‐variant conditions are now associated with CAS either in relative isolation, as in the case of FOXP2 variants, or most typically in association with other neurodevelopmental conditions, such as epilepsy, intellectual disability, motor impairment and autism. CAS requires careful differential diagnosis from other childhood speech disorders, but when a severe and persistent diagnosis is confirmed, a genetic aetiology should increasingly be pursued.

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Section: Genetic Bases Of Casmentioning

confidence: 99%

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

Morgan

Webster

2018

J Paediatrics Child Health

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“…Phenotypic features of CdCS vary depending on deletion size and breakpoints. The critical regions which are responsible for the characteristic cry and the remaining features are well demonstrated in several studies and related to deletion of 5p15.3 and 5p15.2, respectively [Overhauser et al, 1994;Mainardi et al, 2001;Wu et al, 2005;Zhang et al, 2005;Elmakky et al, 2014]. Chromosome 5p deletions not including the critical regions do not represent the characteristics of CdCS as cat-like cry or speech delay.…”

Section: Discussionmentioning

confidence: 86%

“…The critical regions of the syndrome are 5p15.2 and 5p15.3. Deletion of 5p15.3 is responsible for the typical cat-like cry and speech delay, whereas deletion of 5p15.2 is responsible for dysmorphic features, microcephaly, and intellectual disability [Overhauser et al, 1994;Mainardi et al, 2001;Wu et al, 2005;Zhang et al, 2005;Elmakky et al, 2014]. Larger deletions are associated with more severe neurological impairment [Mainardi et al, 2001].…”

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confidence: 99%

Three Offspring with Cri-du-Chat Syndrome from Phenotypically Normal Parents

2020

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Cri-du-chat syndrome is characterized by facial dysmorphism, intellectual disability, and multiple congenital anomalies. Most cases occur de novo. Here, we report 3 siblings with cri-du-chat syndrome born to healthy parents. The proband was admitted to our clinic at the age of 6.5 years due to severe intellectual disability, facial dysmorphism, and heart defect. His karyotype showed a deletion of chromosome 5p. Microarray analysis revealed a 29-Mb deletion in chromosome 5p and a 4.7-Mb duplication in chromosome 19q. FISH analysis indicated an unbalanced translocation between 5p13.3 and 19q13.4. During follow-up, the second and the third child of the family were born with the same chromosome abnormality. Parental peripheral blood and skin fibroblast karyotypes as well as the FISH results using chromosome 5p- and 19q-specific subtelomeric probes were normal. FISH analysis of the father's sperm detected a 5p deletion in 12.8% of 200 cells, and microarray analysis confirmed the same unbalanced chromosome abnormality in a mosaic pattern. Uncultured peripheral blood and buccal smear of the father were also studied by FISH to exclude low-level mosaicism and in vitro culture effect. This is the first study that provides molecular evidence of paternal gonadal mosaicism of an unbalanced translocation detected in 3 siblings with cri-du-chat syndrome.

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“…Therefore, the microdeletion in this family does not appear to include the critical region for the cat-like cry in CdCS [Wu et al, 2005]. Recently, Elmakky et al [2014] reported a small terminal deletion (arr[hg19] 5p15.33p15.32(22,178-5,539,182)x1) due to an unbalanced 5;15 chromosomal translocation causing atypical CdCS phenotypes including cat-like cry [Elmakky et al, 2014]. On the basis of the breakpoints from Family III in our study, along with the proband reported by Elmakky, we narrow down the critical region for catlike cry to a 733.4 Kb region at 5p15.32 (4,805,539,182) encompassing only three genes, LINC01020 (a long noncoding RNA gene), ADAMTS16, and ICE1.…”

Section: Discussionmentioning

confidence: 94%

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

Zhang

Willing

Grange

et al. 2015

American J of Med Genetics Pt A

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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.

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A three-generation family with terminal microdeletion involving 5p15.33–32 due to a whole-arm 5;15 chromosomal translocation with a steady phenotype of atypical cri du chat syndrome

Cited by 33 publications

References 12 publications

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

Three Offspring with Cri-du-Chat Syndrome from Phenotypically Normal Parents

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

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