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A novel 1.4 Mb de novo microdeletion of chromosome 1q21.3 in a child with microcephaly, dysmorphic features and mental retardation

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Sujana Reddy
Sujana Reddy
Sujana Reddy
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Natalia Dolzhanskaya at New York State Institute for Basic Research in Developmental Disabilities
Natalia Dolzhanskaya
Jacquelyn Krogh
Jacquelyn Krogh
Jacquelyn Krogh
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Milen Velinov at Rutgers, The State University of New Jersey
Milen Velinov
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Abstract and Figures

A 2.5 years old girl presented with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. About 1 Mb deletion in the chromosomal region 1q21.3 was identified using BAC array CGH analysis. The parental follow up FISH analysis was normal. Further study of the deletion using a 244K oligo-array of Agilent Technologies Inc., Santa Clara, CA, USA defined the deleted region to span about 1.4 Mb with approximate genomic location chr1:152,511,593-153,993,103 (NCBI genome build 36). This is a novel deletion, not reported to-date. Larger proximal 1q deletions that were previously reported typically included microcephaly, mental retardation and multiple congenital anomalies. The deleted region reported here includes at least 30 coding genes. Among them of interest is a three-gene cluster of the ephrin gene family (EFNA1, EFNA3 and EFNA4). This is a group of receptor protein-tyrosine kinase type genes with presumed, but not completely characterized function in nervous system development.
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Chromosomal imbalance letter
A novel 1.4 Mb de novo microdeletion of chromosome 1q21.3 in a child
with microcephaly, dysmorphic features and mental retardation
Sujana Reddy
a
, Natalia Dolzhanskaya
b
, Jacquelyn Krogh
b
, Milen Velinov
b
,
*
a
Richmond University Medical Center, Staten Island, NY, USA
b
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
article info
Article history:
Received 3 July 2009
Accepted 10 September 2009
Available online 20 September 2009
Keywords:
Microcephaly
Mental retardation
Arching eyebrows
Persistent fetal pads
Clinodactyly
Deletion 1q21.3
Proximal 1q deletion
EFNA1
EFNA3
EFNA4
abstract
A 2.5 years old girl presented with moderate mental retardation, microcephaly, arching eyebrows, low set
ears, long eyelashes, persistent fetal pads and clinodactyly. About 1 Mb deletion in the chromosomal region
1q21.3 was identified using BAC array CGH analysis. Theparental follow up FISHanalysis was normal.Further
study of the deletion using a 244K oligo-array of Agilent Technologies Inc., Santa Clara, CA, USA defined the
deleted region to span about 1.4 Mb with approximate genomic locationchr1:152,511,593-153,993,103 (NCBI
genome build 36). This is a novel deletion, not reported to-date. Larger proximal 1q deletions that were
previously reported typically included microcephaly, mental retardation and multiple congenital anomalies.
The deleted region reported here includes at least 30 coding genes. Among them of interest is a three-gene
cluster of the ephrin gene family (EFNA1,EFNA3 and EFNA4). This is a group of receptor protein-tyrosine
kinase type genes with presumed, but not completely characterized function in nervous system
development.
Ó2009 Elsevier Masson SAS. All rights reserved.
1. Methods of detection
1.1. Cytogenetics
A 475–550 band resolution chromosome analysis revealed an
apparently normal female karyotype of 46,XX.
1.2. Array CGH
Commercial array CGH analysis with 1327 BAC probe array (Quest
Diagnostic Inc., Madison, NJ, USA) identified a deletion at 1q21 of at
least 0.5 Mb involving BAC clones CTD-3186L23 and RP11-313J15.
Additional array CGH analysis using a 244K oligo-array from Agilent
Technologies Inc., Santa Clara, CA, USA (array design ID: 014693) was
then done to better characterize the deleted area (Fig. 1).
1.3. Chromosomal anomaly
The deletion was found to span approximately 1.4 Mb on chro-
mosome 1q21.3 with the proximal deleted probe starting at
chr1:152,511,593, and the distal deleted probe ending at
chr1:153,993,103 (NCBI genome build 36). Parental array CGH analysis
and FISH testing for balanced translocations were normal.
1.4. Method of confirmation
FISH analysis using the deleted BAC probes: CTD-3186L23 and
RP11-313J15.
1.5. Confirmed de novo
Both parents were studied using BAC array analysis and FISH
analysis with the deleted probes with normal results.
2. Clinical description
A 2.5-year-old girl of Middle Eastern (Palestine) origin was
evaluated because of microcephaly and developmental delay. She
was born to non-consanguineous parents. Her mother was 31 years
old and her father was 35 years old at the time of her birth. The
pregnancy was uncomplicated. Use of drugs, alcohol was denied.
She was born via Caesarian section at full term because of fetal
distress. The birth weight was 2650 g. After birth she received some
respiratory support and stayed in the hospital for 3 days. She had
*Corresponding author at: NYS Institute for Basic Research in Developmental
Disabilities, Human Genetics, 1050 Forest Hill Road, Staten Island, New York 10314,
USA. Tel./fax: þ17184945219.
E-mail address: milen.velinov@omr.state.ny.us (M. Velinov).
Contents lists available at ScienceDirect
European Journal of Medical Genetics
journal homepage: http://www.elsevier.com/locate/ejmg
1769-7212/$ – see front matter Ó2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmg.2009.09.003
European Journal of Medical Genetics 52 (2009) 443–445
Author's personal copy
poor feeding and failure to thrive after birth. Developmental delay
was noticed since birth. She was not walking until 18 months of age.
She was non-verbal at her last evaluation at the ageof 3 years and 3
months, and was considered to fall in the range of moderate mental
retardation. She had some tendency for self-mutilation (hitting her
face and banging her head when agitated). She had a poor appetite
and did not gain weight appropriately. At 3 years and 3 months of
age her height was at the 20th percentile, her weight was below
the 3rd percentile, and her head circumference was below the 2nd
percentile for her age. On exam she had decreased eye contact and
dysmorphic facial features with arching eyebrows, full lips and
micrognatia (Fig. 2). She also had a high arched palate, persistent
fetal pads and clinodactyly. She had normal skull X-ray, brain MRI
and cardiac ECHO exams. Her mother had two miscarriages. Her
7-year-old sister and 11-year-old brother were both in good health
and with normal development.
3. Discussion
Proximal 1q (1q21-q25) deletions identifiable on G-banding
present with developmental delay, microcephaly, cardiac, renal and
genital abnormalities, and dysmorphic features [3,5]. Sub-micro-
scopic deletion with similar/identical location and size to the one in
our patient has not been previously reported, including in Decipher
or ECARUCA databases. The phenotype reported here includes some
of the common features of proximal 1q deletions: microcephaly,
developmental delay, clinodactyly and dysmorphic features. It does
not include others: congenital cardiac or genital defects, cleft palate
and brain malformations [3,5]. The deleted region includes at least
30 coding genes. The genes with known function in the central
nervous system are shown in Table 1. Of interest is a three-gene
cluster of the ephrin gene family (EFNA1,EFNA3 and EFNA4). This is
Fig. 1. Chromosome and gene view of the deleted chromosomal region on chromosome 1q (CGH analytics 3.5.14, Agilent Inc.).
Fig. 2. The patient at 2.5 years of age. Facial dysmorphism including arching eyebrows,
full lips and micrognatia is noted.
Table 1
List of genes with known function in the central nervous system, located in the
deleted chromosomal area, and their disease associations.
Gene symbol Gene product/function Disease association
CHRNB2 Neuronal acetylcholine receptor Autosomal dominant
nocturnal frontal lobe
epilepsy.
KCNN3 Regulates neuronal excitability Unknown
EFNA4 Ephrin family receptor
protein-tyrosine kinase,
developmental events in the
nervous system and
in erythropoiesis
Unknown
EFNA3 Same as EFNA4 Unknown
EFNA1 Same as EFNA4 Unknown
AK308965 Same as EFNA4 Unknown
S. Reddy et al. / European Journal of Medical Genetics 52 (2009) 443–445444
Author's personal copy
a group of receptor protein-tyrosine kinase type genes with
presumed, but not completely characterized function in nervous
system development [6]. Mutations of the gene CHRNB2, also located
in the deleted area have been reported in autosomal-dominant
nocturnal epilepsy [7]. To-date no clinical signs of seizure activity
were reported in this patient. Other genes in the deleted area with
known disease associations are HAX1, associated with autosomal
recessive severe congenital neutropenia, also known as Kostmann
disease [2], ADAR, associated with Dyschromatosis symmetrica
hereditaria [4], and PKLR, associated with chronic hereditary non-
spherocytic hemolytic anemia [1]. To-date no specific clinical
manifestations of any of these disorders were noted in this patient.
Acknowledgments
This study was partially supported by the New York State Office
of Mental Retardation and Developmental Disabilities. We thank
Dr. Ed Jenkins for constructive comments during the manuscript
preparation.
References
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A family of ligands has been identified for the largest group of receptor protein-tyrosine kinases--the hitherto 'orphan' EPH receptor subfamily--and the functions of these receptors and ligands are starting to be elucidated.
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CHRNB2 Is the Second Acetylcholine Receptor Subunit Associated with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy*
Article
  • Feb 2001
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.
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A patient defines the interstitial 1q deletion syndrome characterized by Antithrombin III deficiency
Article
  • Jan 2002
A patient with microbrachycephaly, high forehead, long philtrum, thin upper lip, downturned corners of the mouth, low set ears with overlapping helix, fifth-finger clinodactyly, small hands and feet, bilateral transverse palmar crease, low total finger ridge count, hypotonia, severe growth and psychomotor delay, mild hypoplasia of corpus callosum, and Arnold-Chiari type 1 malformation is reported. The karyotype showed 46, XY, del(1)(q23q31.2). Coagulation factor V (F5, 1q23) and coagulation factor XIII (F13B, 1q31-q32.1) levels were normal. As expected, antithrombin III (AT3, 1q23-q25.1) serum level and activity were half of normal. We performed a review of the literature on proximal and intermediate deletion 1q syndrome, and we hypothesize the existence of only one 1q interstitial deletion syndrome, clinically characterized by ATIII deficiency.
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Mutations of the RNA-Specific Adenosine Deaminase Gene (DSRAD) Are Involved in Dyschromatosis Symmetrica Hereditaria
Article
  • Oct 2003
Dyschromatosis symmetrica hereditaria (DSH) (also called "reticulate acropigmentation of Dohi") is a pigmentary genodermatosis of autosomal dominant inheritance characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal aspects of the hands and feet. To determine the gene responsible for this disease, we performed a genomewide search in three families with DSH and mapped the DSH locus to chromosome 1q21.3. The mutations involved in causing DSH have been identified in the gene that encodes double-stranded RNA-specific adenosine deaminase (DSRAD) as the disease gene.
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  • Jan 2007
  • Nat Genet
  • 86-92
  • C Klein
  • M Grudzien
  • G Appaswamy
  • M Germeshausen
  • I Sandrock
  • A A Schaffer
  • C Rathiam
  • K Boztug
  • B Schwinzer
  • N Rezaei
  • G Bohn
  • M Melin
  • G Carlsson
  • B Fadeel
  • N Dahl
  • J Palmblad
  • J I Henter
  • C Zeidler
  • B Grimbacher
  • K Welte
C. Klein, M. Grudzien, G. Appaswamy, M. Germeshausen, I. Sandrock, A.A. Schaffer, C. Rathiam, K. Boztug, B. Schwinzer, N. rezaei, G. Bohn, M. Melin, G. Carlsson, B. Fadeel, N. Dahl, J. Palmblad, J.I. Henter, C. Zeidler, B. Grimbacher, K. Welte, HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat. Genet. 39 (2007) 86-92.
A patient defines the interstitial 1q deletion syndrome characterized by antitrombin III deficiency
  • Jan 2001
  • 282-286
  • R Palotta
  • L Dalpra
  • M Miozzo
  • T Ehresmann
  • P Fusilli
R. Palotta, L. Dalpra, M. Miozzo, T. Ehresmann, P. Fusilli, A patient defines the interstitial 1q deletion syndrome characterized by antitrombin III deficiency. Am. J. Med. Genet. 104 (2001) 282-286.
A patient defines the interstitial 1q deletion syndrome characterized by antitrombin III deficiency
  • Jan 2001
  • 282
  • Palotta