A Losada

A Musio

D Dorsett

D Dorsetta

ET Tonkin

Gholamreza Mohamadian

H Uzun

Habibolah Nazem

Hamid Galehdari

I Barisic

ID Krantz

JA Horsfield

JE Allanson

KL Russell

L Jackson

LA Gillis

MA Deardorff

MG Vrouwe

Mohammad Pedram

P Jahnke

Roya Monajemzadeh

T Hirano

Journal of Medical Case Reports

English

PubMed

Springer - Publisher Connector

CASE REPORT Open Access
Identification of a novel de novo mutation in the
NIPBL gene in an Iranian patient with Cornelia
de Lange syndrome: A case report
Hamid Galehdari1*, Roya Monajemzadeh2, Habibolah Nazem2, Gholamreza Mohamadian3 and
Mohammad Pedram4
Abstract
Background: Cornelia de Lange syndrome is characterized by dysmorphic facial features, hirsutism, severe growth
and developmental delay. Germline mutations in the NIPBL gene with an autosomal dominant pattern and in the
SMC1A gene with an X-linked pattern have been identified in Cornelia de Lange syndrome.
Case presentation: A two-month-old Iranian boy who showed multiple congenital anomalies was referred to the
genetic center of a welfare organization in southwest Iran. He was the second child of a non-consanguineous
marriage, born after full term with normal delivery. His birth weight was 3110 g, his length was 46 cm and his
head circumference was 30 cm. Both parents were clinically asymptomatic, with no positive history of any
deformity in their respective families.
Conclusions: Sequencing of the NIPBL gene from our patient revealed a single-base deletion of thymidine in exon
10 (c.516delT). This mutation presumably results in premature termination at codon 526. We did not observe this
mutation in the parents of our patient with Cornelia de Lange syndrome. The results presented here enlarge the
spectrum of NIPBL gene mutations associated with Cornelia de Lange syndrome by identifying a novel de novo
mutation in an Iranian patient with Cornelia de Lange syndrome and further support the hypothesis that NIPBL
mutations are disease-causing mutations leading to Cornelia de Lange syndrome.
Introduction
Cornelia de Lange syndrome (CdLS; http://www.ncbi.
nlm.nih.gov/omim/122470), also known as Brachmann-
de Lange syndrome, is a clinically and genetically
heterogeneous developmental disorder characterized by
growth and mental retardation [1,2]. The prevalence of
mild and classic CdLS is estimated to be as high as 1.6
to 2.2/100,000 births [3]. Growth retardation is an
almost universal finding in patients with CdLS and typi-
cally has a pre-natal onset. Mental retardation in
patients with CdLS is often severe, resulting in a mean
IQ of 53 [1]. Many patients also demonstrate autism-
like behavior and self-injurious behavior [4]. No gender-
based predilection has been reported, and no differences
linked to maternal age or race has been described [3].
The majority of cases are sporadic, and very few familial
cases of CdLS have been reported [4]. Pedigree analyses
of several families have demonstrated autosomal
dominant inheritance with both maternal and paternal
transmission [5].
Multiple genes are considered to be responsible for
CdLS, all of which are implicated in sister chromatid
cohesion [6]. Mutations in the NIPBL gene on chromo-
some 5p13.1 account for approximately 50% of CdLS
cases and have been shown to cause both mild and
severe forms of the disease [1]. The NIPBL gene is 9.5
kbp in length and contains 47 exons that encode two
isoforms of 2804 and 2697 amino acids, termed delan-
gin-A and delangin-B, respectively [1]. The human
NIPBL proteins share homology with Drosophila mela-
nogaster Nipped-B and Scc2 from the budding yeast
Saccharomyces cerevisiae [6]. The NIPBL protein is
directly associated with chromatin while playing a role
in the loading of the cohesin complex that mediates
* Correspondence: galehdari187@yahoo.com
1Genetics Department, Shahid Chamran University, Ahwaz, Iran
Full list of author information is available at the end of the article
Galehdari et al. Journal of Medical Case Reports 2011, 5:242
http://www.jmedicalcasereports.com/content/5/1/242 JOURNAL OF MEDICAL
CASE REPORTS
© 2011 Galehdari et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
sister chromatid cohesion to chromosomes. It also has a
dose-dependent gene-regulatory function [7]. Further-
more, mutations in the SMC1A gene cause an X-linked
form of CdLS [8]. Mutations in the SMC3 gene on chro-
mosome 10 have also been reported to cause CdLS [9].
The SMC1A and SMC3 genes encode the two mitotic
cohesion subunits [10]. Cohesin plays a role in sister
chromatid cohesion during mitosis and meiosis, in DNA
repair and in gene expression [11]. Evidence that cohe-
sin regulates gene expression is accumulating rapidly
[12-14] and supports the hypothesis that developmental
deficits in patients with CdLS likely arise from changes
in cohesin-regulated gene expression that alter tran-
scription in multiple ways [15,16]. Here, we report the
first molecular analysis of the NIPBL gene in an Iranian
newborn baby diagnosed with CdLS.
Case presentation
A two-month-old Iranian boy with multiple congenital
anomalies was referred to the genetic center of a welfare
organization in Ahwaz (southwestern Iran).
Medical history
At birth, our patient exhibited arch-like confluent
(synophrys) eyebrows; long, curly eyelashes; low anterior
and posterior hairlines; long philtrum; anteverted nares;
depressed nasal bridge; downturned corners of the
mouth and thin lips; a high-arched palate; micrognathia;
and low-set ears. He also had microcephaly; small
hands, with the right hand missing one digit and the left
hand having fused digits; hypertonicity; excessive body
hair (hirsutism) on the back and feet; cryptorchidism; a
small penis; and a low-pitched cry (Figure 1). Echocar-
diography revealed both an atrial septal defect and a
ventricular septal defect in the newborn. Results of
kidney sonography were normal. A computed tomogra-
phy (CT) scan of the brain showed subarachnoid
hemorrhage (SAH) and intra-ventricular hemorrhage
(IVH) with no sign of hydrocephalus.
Family history
Our patient was the second child of a non-consanguineous
marriage, born after full term by normal delivery, with a
birth weight of 3110 g, length of 46 cm and head circum-
ference of 30 cm. Both parents were clinically asympto-
matic, with no positive history of any deformity in their
respective families.
Discussion
Three family members (our patient and his parents)
were included in this study after informed consent was
obtained. Genomic DNA was extracted using a standard
protocol, and 46 coding exons (from exons 2 to 47) of
the NIPBL gene were amplified by polymerase chain
reaction assay as described previously [2]. Direct
sequencing of the coding exons along with the flanking
intron regions of the NIPBL gene was performed using
the Big Dye Terminator Cycle Sequencing Ready Reac-
tion Kit (Applied Biosystems; Darmstadt, Germany) on
an ABI Prism 3700 automated genetic analyzer (Applied
Biosystems).
Direct sequencing analysis of the proband demon-
strated a heterozygous, single-nucleotide deletion
(c.516delT) in exon 10 of the NIPBL gene, which
resulted in a frame shift, leading to premature termina-
tion at codon 526 (Figure 2). Because of the absence of
this mutation in the parents of our patient, we report
here a novel de novo mutation of the NIPBL gene. To
support the pathogenic nature of this mutation, we
searched the genomes of 45 healthy individuals for simi-
lar mutations the NIPBL gene, with negative results.
Conclusions
The clinical features of CdLS vary widely among
patients, ranging from the classic form, which is severe,
to mild forms and including some individuals who have
non-syndromic phenotypes but some form of mental
retardation [17]. In spite of the differences in severity,
the facial dysmorphisms have provided the most helpful
Figure 1 Characteristic features of Cornelia de Lange syndrome. (A) Hirsutism. (B,C) Variability of upper-limb abnormalities (distal reduction
defect with missing and fused digits in the same child).
Galehdari et al. Journal of Medical Case Reports 2011, 5:242
http://www.jmedicalcasereports.com/content/5/1/242
Page 2 of 4
features in establishing a diagnosis [4]. In patients with a
mild clinical presentation, the characteristic facial
appearance may not develop until two to three years of
age, while it is always present at birth in the severe form
[18]. Structural malformations primarily affect the ulnar
aspects of the upper limbs and can range from severe
reduction defects, with almost complete absence of the
forearms, to small hands with fifth-finger clinodactyly
and proximally placed thumbs. Developmental delays
and mental retardation are generally moderate to severe.
With the aid of molecular analyses, it has recently been
recognized that many patients with mild CdLS display
primarily mental retardation without substantial struc-
tural differences [18].
Numerous studies have indicated that mutations in
NIPBL cause both mild and severe forms of CdLS [1,2].
These mutations may cause loss-of-function alleles, and
the severity of the syndrome generally correlates with
the type of mutation [1]. More severe mutations of the
NIPBL gene, including deletions, cause more severe
disease phenotypes than missense mutations [1]. In con-
trast, mutations in the SMC3 and SMC1A genes occur
in patients with a mild CdLS clinical presentation,
including mild facial structural anomalies, no absence or
reduction of limbs or digits, no other major structural
anomalies or, in some instances, mild to moderate men-
tal retardation with a non-syndromic phenotype [9].
Here, we describe the first molecular genetics diagno-
sis of an Iranian patient with classic (severe) CdLS. Our
patient exhibited characteristic clinical signs of severe
CdLS (distinctive facial appearance, limb reduction,
microcephaly, short neck and hirsutism). The severity of
CdLS in our patient correlates with previous genetic
observations in other patients and supports the NIPBL
mutation described here as the disease-causing mutation
in our patient. The single-nucleotide deletion (c.516delT)
in exon 10 described here is, according to information
available in the Human Genome Mutation Database [19]
and, to the best of our knowledge, a novel heterozygous
mutation in the NIPBL gene. Since both parents of our
patient lack this mutation, it strongly suggests that this
mutation arose de novo in our patient. Studies including
more patients with CdLS in Iran are required to assess
the prevalence of this and other NIPBL mutations in the
Iranian population and their importance for CdLS
pathogenesis.
Consent
Written informed consent was obtained from the
patient’s next-of-kin for publication of this case report
and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of
this journal.
Acknowledgements
We thank the Iranian family of the two-month-old boy for consenting to
participate in this study and Mr Baha Salehi for valuable technical assistance.
Author details
1Genetics Department, Shahid Chamran University, Ahwaz, Iran.
2Biochemistry Department, Payamenoor University, Tehran, Iran. 3Genetic
Figure 2 Sequencing of the NIPBL gene. (A) Chromograph from the affected individual showing a heterozygous deletion of a thymidine (-T)
at codon 516 (black arrow). (B) Chromograph from a healthy individual with a wild-type sequence. Letters between both chromographs indicate
the partial cDNA sequence of the NIPBL gene with corresponding codons beginning with codon 511.
Galehdari et al. Journal of Medical Case Reports 2011, 5:242
http://www.jmedicalcasereports.com/content/5/1/242
Page 3 of 4
Center, Welfare Organization, Khuzestan, Ahwaz, Iran. 4Research Center for
Hemoglobinopathies and Thalassemia, Ahwaz, Iran.
Authors’ contributions
HG designed the molecular genetic studies and drafted the manuscript. RM
carried out the molecular genetic studies and participated in writing the
manuscript. GM made the diagnosis. HZ participated in diagnosis and
manuscript editing. MP supervised the study. All authors read and approved
the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 8 February 2010 Accepted: 27 June 2011
Published: 27 June 2011
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doi:10.1186/1752-1947-5-242
Cite this article as: Galehdari et al.: Identification of a novel de novo
mutation in the NIPBL gene in an Iranian patient with Cornelia de
Lange syndrome: A case report. Journal of Medical Case Reports 2011
5:242.
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Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report

Crossref

Adherin: key to the cohesion ring and Cornelia de Lange syndrome. Curr Biol

At the heart of the chromosome: SMC proteins in action. Nat Rev Mol Cell Biol

Cohesin regulation: fashionable ways to wear a ring. Chromosoma

Darroudi F: Increased DNA damage sensitivity of Cornelia de Lange syndrome cells: evidence for impaired recombinational repair. Hum Mol Genet

De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.

doi:10.1186/1752-1947-5-242 Cite this article as: Galehdari et al.: Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report.

Effects of sister chromatid cohesion proteins on cut gene expression during wing development in Drosophila. Development

EUROCAT Working Group: Descriptive epidemiology of Cornelia de Lange syndrome in Europe. Am J Med Genet A

FJ: The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications. Nucleic Acids Res

ID: Dominant paternal transmission of Cornelia de Lange syndrome: a new case and review of 25 previously reported familial recurrences.

ID: Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.

ID: NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

ID: On the molecular etiology of Cornelia de Lange syndrome.

Kocabay K: A newborn with Cornelia de Lange syndrome: a case report. Cases J

LG: Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet

PS: Cohesin dependent regulation of Runx genes. Development

S: de Lange syndrome: a clinical review of 310 individuals.

T: NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet

file:///data/core-remote/dit/data/Springer-OA/pdf/f62/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTc1Mi0xOTQ3LTUtMjQyLnBkZg==.pdf

Identification of a novel de novo mutation in the NIPBL gene in an Iranian patient with Cornelia de Lange syndrome: A case report

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