1p Microdeletion in Sibs With MinimalPhenotypic Manifestations

Jose E. Martínez,1* Cathy M. Tuck-Muller,1 William Gasparrini,2 Shibo Li,1 andWladimir Wertelecki1

1Department of Medical Genetics, University of South Alabama, College of Medicine, Mobile, Alabama2Applied Psychology Center, P.C., Biloxi, Mississippi

We report on two sibs with a paracentric in-version of chromosome 1 [inv(1)(p22.3p34.1)]and a small deletion of the same chromo-some (p34.1→p34.3). They presented withlearning disabilities and disturbed conductbut lacked the more severe manifestationsusually associated with autosomal chromo-some deletion. Born to an alcoholic motherand later placed in foster care because ofabuse and neglect, the behavior abnormali-ties they present are likely to be associatedwith their traumatic postnatal experience.Microscopic deletions without significantmorphological phenotypic expression havebeen described but are rarely reported.Most reported cases of interstitial deletionof 1p had associated malformations and psy-chomotor retardation. These sibs may rep-resent the first evidence that deletion of1p34.1→1p34.3 may have little impact on thephenotype. Am. J. Med. Genet. 82:107–109,1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: chromosome 1p deletion;chromosome 1p inversion;learning disabilities; behav-ior abnormalities; minimalphenotypic manifestations

INTRODUCTION

As a rule, patients with microscopically visible auto-somal deletions have moderate to severe clinical mani-festations, often including malformations, growth fail-ure and mental retardation. Only four such deletionshave thus far been reported in individuals with normalphenotypes. Furthermore, interstitial deletions of theshort arm of chromosome 1 have been found to be as-

sociated with structural anomalies and/or psychomotorretardation in all previously reported cases. We reportan additional deletion (1p34.1→1p34.3) which appearsto cause minimal clinical manifestations.

CLINICAL REPORT

A 13-year-old white boy was referred following anevaluation for attention deficit disorder, disturbed con-duct and symptoms of depression which were attrib-uted to his abandonment by his alcoholic mother. Thesuspected diagnosis was fetal alcohol syndrome.

Growth was normal: OFC 54 cm (50th centile);height 159 cm (50th centile); weight 45 kg (50th cen-tile). He had mild epicanthus bilaterally, prominentnasal bridge, short and deep philtrum and mild pectusexcavatum. A normal for age sexual maturity stage(Tanner II) was noted. Intelligence testing at age 8years showed normal intelligence (WISC-R full scaleIQ 100, verbal IQ 88, and performance IQ 114). Aca-demic achievement tests showed evidence of a severelearning disability, especially for reading (WRAT-Rstandard scores: reading 50, spelling 59, and arithme-tic 78). The psychological evaluation also suggestedsymptoms of attention deficit hyperactivity disorderand adjustment disorder with mixed disturbance ofemotions and conduct.

The patient’s 8-year-old sister, the product of the sec-ond pregnancy, had also been in foster care since age 3years. Her medical history was unremarkable and thephysical examination showed a well-developed childwith minor anomalies similar to those of the patient(bilateral epicanthus, prominent nasal bridge, promi-nent central upper incisors and narrow bifrontal diam-eter). Her growth parameters were normal: OFC 51 cm(50th centile); height 133 cm (50th centile) and weight30 kg (50th centile). Her foster mother described her asshowing almost all of the symptoms of ADHD. Herclinical psychological evaluation showed a characteris-tic pattern of oppositional defiant disorder, as well asmixed disturbance of emotions and conduct. A Full-Scale IQ measured on the WISC-III Scale was esti-mated at 93 (Verbal IQ of 97 and Performance IQ of91). Academic achievement tests were found to be nor-mal (WRAT-III standard scores: reading 99, spelling104, arithmetic 110).

*Correspondence to: Jose E. Martínez, M.D., Department ofMedical Genetics, University of South Alabama, CCCB 290, 307University Boulevard, Mobile, AL 36688-0002.

Received 25 September 1997; Accepted 1 October 1998

American Journal of Medical Genetics 82:107–109 (1999)

© 1999 Wiley-Liss, Inc.

CYTOGENETIC AND FLUORESCENCE IN SITUHYBRIDIZATION (FISH) STUDIES

Chromosome analysis was performed on peripheralblood lymphocytes from the index case and his sister.The propositus was found to have an abnormal chro-mosome 1 (Fig. 1) which appeared to have both a para-centric inversion (1p22.3→1p34.1) and a small deletionin the short arm (1p34.1→1p34.3). The deletion wascontiguous with the distal breakpoint of the inversion.The karyotype of the propositus is described as46,XY,der(1)inv(1)(p22.3p34.1)del(1)(p34.1p34.3). The

same abnormality was identified in his sister. Al-though neither parent was available for study, we as-sume that the derivative chromosome 1 is inheritedand not de novo.

FISH analysis to rule out a cryptic translocation orinsertion was performed using a biotinylated paintingprobe specific for chromosome 1. The probe (COATA-SOME™1, p5205-DG.5) was purchased from Oncor(Gaithersburg, MD) and used according to the manu-facturer’s instructions with minor modifications. Theprobe was hybridized overnight and detected by fluo-rescein-labeled avidin with a single round of amplifica-tion of anti-avidin antibody. The slides were examinedusing a Zeiss Axioskop microscope with FITC filters.

Only the two homologues of chromosome 1 werepainted with the probe without hybridization to anyother chromosome (Fig. 2a,b), ruling out both a cryptictranslocation of the deleted fragment (1p34.1→1p34.3)to another chromosome and insertion of material fromother chromosomes into the derivative chromosome 1.FISH probes specific for the breakpoint regions couldoffer additional information to the interpretation of therearrangement but are not commercially available.

The lack of remaining material from the sibs pre-vented us from pursuing further molecular studies,and the family has been lost to follow up.

DISCUSSION

Normal phenotypes have been reported in associa-tion with only a few microscopically visible autosomaldeletions. Couturier et al. [1985] described a pheno-typically normal mother and son with deletion of band13q21. Overhauser et al. [1986] studied a three-generation family in which six phenotypically normalindividuals had a deletion of band 5p14. Normal phe-notype was also found in association with a deletion ofband 16q21 in three members of a two-generation pedi-gree [Witt et al., 1988]. Prenatal detection of an inter-stitial 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 de-letion was confirmed in peripheral blood lymphocytes(the mother and a previous child, both also phenotypi-cally normal, had the same deletion). Each of the abovedeletions, as well as the deletion reported here, involveloss of a G-dark band. The mild clinical spectra of in-dividuals with these deletions suggest a paucity oftranscribed DNA sequences in these bands.

In regard to chromosome 1, at least 12 cases withdeletions of the short arm and without any other chro-mosomal imbalance have been described in the litera-ture [reviewed by Stockton et al., 1997]. All of thesepatients had multiple congenital abnormalities, anddevelopmental delay/mental retardation was apparentin all survivors.

Only three of these deletions overlap the deletiondetected in our patients. Aarskog [1968] reported alarge deletion of 1p in a male infant with hypotonia,failure to thrive and multiple congenital anomalies, in-

Fig. 1. Idiogram (a) and partial karyotypes demonstrating theinversion and deletion in chromosome 1 in the propositus (b)and his sister (c). The abnormal chromosome is described asder(1)inv(1)(p22.3p34.1)del(1)(p34.1p34.3).

108 Martínez et al.

cluding microcephaly, low-set ears with absent lobes,high arched palate, slanting palpebral fissures, flexioncontractures of the fingers, and bilateral equinovarus.Due to the lack of banding, the breakpoints in 1p werenot determined. However, a terminal deletion wouldplace the breakpoint approximately in band p22. Asmaller terminal deletion (1p34→1pter) was described[Palova et al., 1985] in a 9-year-old boy with severemental retardation, microcephaly, low-set ears, higharched palate, cryptorchidism and hypertrichosis.Howard and Porteus [1990] reported on an interstitialdeletion 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 ofthe overlapping deletions previously reported whichmay account for its modest teratogenetic effects. Ourpatients lack the multiple malformations and mentalretardation described in other patients with deletionsof 1p. Although they have behavioral problems andlearning disabilities, probably a reflection of severe pa-rental abuse and neglect, the sibs reported on herehave normal intelligence.

ACKNOWLEDGMENTS

We thank Ewellonda R. Rowley for her help withlaboratory techniques and Mae Jean Reeves for orga-nizing and typing the manuscripts.

REFERENCESAarskog D. 1968. A large deletion of chromosome no. 1 (46,XY,1?–). J Med

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Barber JCK, Mahl H, Portch J, Crawfurd MD’A. 1991. Interstitial dele-tions without phenotypic effect: prenatal diagnosis of a new family andbrief review. Prenat Diagn 11:411–416.

Couturier J, Morichon-Delvallez N, Dutrillaux B. 1985. Deletion of band13q21 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. Molecularanalysis of an unbalanced deletion of the short arm of chromosome 5that produces no phenotype. Am J Hum Genet 39:1–10.

Palova A, Halasova E, Kamenicka E, Kadasi L. 1985. De novo deletion1p(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 theshort 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 withnormal phenotype: relationship to late replicating DNA. Am J HumGenet 43:A127.

Fig. 2. FISH study of (a) the propositus and (b) the sister using chromosome 1 painting probe. Regions of less intense hybridization present athomologous bands on both copies of chromosome 1 are the result of nonhomogeneous hybridization typical of this probe.

1p Microdeletion in Sibs 109