Dataset Information

Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability.

ABSTRACT: BACKGROUND:Intellectual disability affects approximately 1 to 3% of the general population. The etiology is still poorly understood and it is estimated that one-half of the cases are due to genetic factors. Cryptic subtelomeric aberrations have been found in roughly 5 to 7% of all cases. METHODS:We performed a subtelomeric FISH analysis on 76 unrelated children with normal standard karyotype ascertained by developmental delay or intellectual disability, associated with congenital malformations, and/or facial dysmorphisms. RESULTS:Ten cryptic chromosomal anomalies have been identified in the whole cohort (13,16%), 8 in the group of patients characterized by developmental delay or intellectual disability associated with congenital malformations and facial dysmorphisms, 2 in patients with developmental delay or intellectual disability and facial dysmorphisms only. CONCLUSION:We demonstrate that a careful clinical examination is a very useful tool for pre-selection of patients for genomic analysis, clearly enhancing the chromosomal anomaly detection rate. Clinical features of most of these patients are consistent with the corresponding emerging chromosome phenotypes, pointing out these new clinical syndromes associated with specific genomic imbalances.

SUBMITTER: Belligni EF

PROVIDER: S-EPMC2687548 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability.

Belligni Elga F EF Biamino Elisa E Molinatto Cristina C Messa Jole J Pierluigi Mauro M Faravelli Francesca F Zuffardi Orsetta O Ferrero Giovanni B GB Silengo Margherita Cirillo MC

Italian journal of pediatrics 20090427 1

<h4>Background</h4>Intellectual disability affects approximately 1 to 3% of the general population. The etiology is still poorly understood and it is estimated that one-half of the cases are due to genetic factors. Cryptic subtelomeric aberrations have been found in roughly 5 to 7% of all cases.<h4>Methods</h4>We performed a subtelomeric FISH analysis on 76 unrelated children with normal standard karyotype ascertained by developmental delay or intellectual disability, associated with congenital ...[more]

PMID: 19490664

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Project description:INTRODUCTION:Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. METHODS:Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS:Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. CONCLUSIONS:These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

Project description:Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID. Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID. Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing. Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1, or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID. Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.

Dataset Information

Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability.

Publications

Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability.

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