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1p microdeletion in sibs with minimal phenotypic manifestations

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American Journal of Medical Genetics 82:107–109 (1999)
1p Microdeletion in Sibs With Minimal
Phenotypic Manifestations
José E. Martínez,1* Cathy M. Tuck-Muller,1 William Gasparrini,2 Shibo Li,1 and
Wladimir Wertelecki1
1
Department of Medical Genetics, University of South Alabama, College of Medicine, Mobile, Alabama
Applied Psychology Center, P.C., Biloxi, Mississippi
2
We report on two sibs with a paracentric inversion of chromosome 1 [inv(1)(p22.3p34.1)]
and a small deletion of the same chromosome (p34.1→p34.3). They presented with
learning disabilities and disturbed conduct
but lacked the more severe manifestations
usually associated with autosomal chromosome deletion. Born to an alcoholic mother
and later placed in foster care because of
abuse and neglect, the behavior abnormalities they present are likely to be associated
with their traumatic postnatal experience.
Microscopic deletions without significant
morphological phenotypic expression have
been described but are rarely reported.
Most reported cases of interstitial deletion
of 1p had associated malformations and psychomotor retardation. These sibs may represent the first evidence that deletion of
1p34.1→1p34.3 may have little impact on the
phenotype. Am. J. Med. Genet. 82:107–109,
1999. © 1999 Wiley-Liss, Inc.
KEY WORDS: chromosome 1p deletion;
chromosome 1p inversion;
learning disabilities; behavior abnormalities; minimal
phenotypic manifestations
INTRODUCTION
As a rule, patients with microscopically visible autosomal deletions have moderate to severe clinical manifestations, often including malformations, growth failure and mental retardation. Only four such deletions
have thus far been reported in individuals with normal
phenotypes. Furthermore, interstitial deletions of the
short arm of chromosome 1 have been found to be as-
*Correspondence to: José E. Martínez, M.D., Department of
Medical Genetics, University of South Alabama, CCCB 290, 307
University Boulevard, Mobile, AL 36688-0002.
Received 25 September 1997; Accepted 1 October 1998
© 1999 Wiley-Liss, Inc.
sociated with structural anomalies and/or psychomotor
retardation in all previously reported cases. We report
an additional deletion (1p34.1→1p34.3) which appears
to cause minimal clinical manifestations.
CLINICAL REPORT
A 13-year-old white boy was referred following an
evaluation for attention deficit disorder, disturbed conduct and symptoms of depression which were attributed to his abandonment by his alcoholic mother. The
suspected diagnosis was fetal alcohol syndrome.
Growth was normal: OFC 54 cm (50th centile);
height 159 cm (50th centile); weight 45 kg (50th centile). He had mild epicanthus bilaterally, prominent
nasal bridge, short and deep philtrum and mild pectus
excavatum. A normal for age sexual maturity stage
(Tanner II) was noted. Intelligence testing at age 8
years showed normal intelligence (WISC-R full scale
IQ 100, verbal IQ 88, and performance IQ 114). Academic achievement tests showed evidence of a severe
learning disability, especially for reading (WRAT-R
standard scores: reading 50, spelling 59, and arithmetic 78). The psychological evaluation also suggested
symptoms of attention deficit hyperactivity disorder
and adjustment disorder with mixed disturbance of
emotions and conduct.
The patient’s 8-year-old sister, the product of the second pregnancy, had also been in foster care since age 3
years. Her medical history was unremarkable and the
physical examination showed a well-developed child
with minor anomalies similar to those of the patient
(bilateral epicanthus, prominent nasal bridge, prominent central upper incisors and narrow bifrontal diameter). Her growth parameters were normal: OFC 51 cm
(50th centile); height 133 cm (50th centile) and weight
30 kg (50th centile). Her foster mother described her as
showing almost all of the symptoms of ADHD. Her
clinical psychological evaluation showed a characteristic pattern of oppositional defiant disorder, as well as
mixed disturbance of emotions and conduct. A FullScale IQ measured on the WISC-III Scale was estimated at 93 (Verbal IQ of 97 and Performance IQ of
91). Academic achievement tests were found to be normal (WRAT-III standard scores: reading 99, spelling
104, arithmetic 110).
108
Martínez et al.
CYTOGENETIC AND FLUORESCENCE IN SITU
HYBRIDIZATION (FISH) STUDIES
Chromosome analysis was performed on peripheral
blood lymphocytes from the index case and his sister.
The propositus was found to have an abnormal chromosome 1 (Fig. 1) which appeared to have both a paracentric inversion (1p22.3→1p34.1) and a small deletion
in the short arm (1p34.1→1p34.3). The deletion was
contiguous with the distal breakpoint of the inversion.
The karyotype of the propositus is described as
46,XY,der(1)inv(1)(p22.3p34.1)del(1)(p34.1p34.3). The
same abnormality was identified in his sister. Although neither parent was available for study, we assume that the derivative chromosome 1 is inherited
and not de novo.
FISH analysis to rule out a cryptic translocation or
insertion was performed using a biotinylated painting
probe specific for chromosome 1. The probe (COATASOME™1, p5205-DG.5) was purchased from Oncor
(Gaithersburg, MD) and used according to the manufacturer’s instructions with minor modifications. The
probe was hybridized overnight and detected by fluorescein-labeled avidin with a single round of amplification of anti-avidin antibody. The slides were examined
using a Zeiss Axioskop microscope with FITC filters.
Only the two homologues of chromosome 1 were
painted with the probe without hybridization to any
other chromosome (Fig. 2a,b), ruling out both a cryptic
translocation of the deleted fragment (1p34.1→1p34.3)
to another chromosome and insertion of material from
other chromosomes into the derivative chromosome 1.
FISH probes specific for the breakpoint regions could
offer additional information to the interpretation of the
rearrangement but are not commercially available.
The lack of remaining material from the sibs prevented us from pursuing further molecular studies,
and the family has been lost to follow up.
DISCUSSION
Fig. 1. Idiogram (a) and partial karyotypes demonstrating the
inversion and deletion in chromosome 1 in the propositus (b)
and his sister (c). The abnormal chromosome is described as
der(1)inv(1)(p22.3p34.1)del(1)(p34.1p34.3).
Normal phenotypes have been reported in association with only a few microscopically visible autosomal
deletions. Couturier et al. [1985] described a phenotypically normal mother and son with deletion of band
13q21. Overhauser et al. [1986] studied a threegeneration family in which six phenotypically normal
individuals had a deletion of band 5p14. Normal phenotype was also found in association with a deletion of
band 16q21 in three members of a two-generation pedigree [Witt et al., 1988]. Prenatal detection of an interstitial deletion of the short arm of chromosome 11
(11p12) was reported by Barber et al. [1991]. At term,
a phenotypically normal girl was delivered and the deletion was confirmed in peripheral blood lymphocytes
(the mother and a previous child, both also phenotypically normal, had the same deletion). Each of the above
deletions, as well as the deletion reported here, involve
loss of a G-dark band. The mild clinical spectra of individuals with these deletions suggest a paucity of
transcribed DNA sequences in these bands.
In regard to chromosome 1, at least 12 cases with
deletions of the short arm and without any other chromosomal imbalance have been described in the literature [reviewed by Stockton et al., 1997]. All of these
patients had multiple congenital abnormalities, and
developmental delay/mental retardation was apparent
in all survivors.
Only three of these deletions overlap the deletion
detected in our patients. Aarskog [1968] reported a
large deletion of 1p in a male infant with hypotonia,
failure to thrive and multiple congenital anomalies, in-
1p Microdeletion in Sibs
109
Fig. 2. FISH study of (a) the propositus and (b) the sister using chromosome 1 painting probe. Regions of less intense hybridization present at
homologous bands on both copies of chromosome 1 are the result of nonhomogeneous hybridization typical of this probe.
cluding microcephaly, low-set ears with absent lobes,
high arched palate, slanting palpebral fissures, flexion
contractures of the fingers, and bilateral equinovarus.
Due to the lack of banding, the breakpoints in 1p were
not determined. However, a terminal deletion would
place the breakpoint approximately in band p22. A
smaller terminal deletion (1p34→1pter) was described
[Pálová et al., 1985] in a 9-year-old boy with severe
mental retardation, microcephaly, low-set ears, high
arched palate, cryptorchidism and hypertrichosis.
Howard and Porteus [1990] reported on an interstitial
deletion of the short arm of chromosome 1
(p34.1→p36.1) in a male infant with growth failure,
microcephaly, low-set ears, narrow palpebral fissures,
high arched palate, cryptorchidism, hypertrichosis,
and pulmonary atresia with a ventricular septal defect.
The deletion described here is smaller than any of
the overlapping deletions previously reported which
may account for its modest teratogenetic effects. Our
patients lack the multiple malformations and mental
retardation described in other patients with deletions
of 1p. Although they have behavioral problems and
learning disabilities, probably a reflection of severe parental abuse and neglect, the sibs reported on here
have normal intelligence.
ACKNOWLEDGMENTS
We thank Ewellonda R. Rowley for her help with
laboratory techniques and Mae Jean Reeves for organizing and typing the manuscripts.
REFERENCES
Aarskog D. 1968. A large deletion of chromosome no. 1 (46,XY,1?–). J Med
Genet 5:322–325.
Barber JCK, Mahl H, Portch J, Crawfurd MD’A. 1991. Interstitial deletions without phenotypic effect: prenatal diagnosis of a new family and
brief review. Prenat Diagn 11:411–416.
Couturier J, Morichon-Delvallez N, Dutrillaux B. 1985. Deletion of band
13q21 is compatible with normal phenotype. Hum Genet 70:87–91.
Howard PJ, Porteus M. 1990. Deletion of chromosome 1p: a short review.
Clin Genet 37:127–131.
Overhauser J, Golbus MS, Schonberg SA, Wasmuth JJ. 1986. Molecular
analysis of an unbalanced deletion of the short arm of chromosome 5
that produces no phenotype. Am J Hum Genet 39:1–10.
Pálová A, Halasová E, Kamenická E, Kádasi L. 1985. De novo deletion
1p(34→pter). Hum Genet 69:94.
Stockton DW, Ross HL, Bacino CA, Altman CA, Shaffer LG, Lupski JR.
1997. Severe clinical pheonotype due to an interstitial deletion of the
short arm of chromosome 1: a brief review. Am J Med Genet 71:189–
193.
Witt DR, Lew SP, Mann J. 1988. Heritable deletion of band 16q21 with
normal phenotype: relationship to late replicating DNA. Am J Hum
Genet 43:A127.
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