Microduplications are a type of genetic mutation, that result from the duplication of a small part of a chromosome. They are typically one to three megabases long, they involve several contiguous genes and represent the reciprocal product of duplicon mediated non-allelic homologous recombinations, a mechanism which often lead to microdeletions.Their location is extremely variable, even if a specific "critical region" may be consistently involved.
Lots of phenotypic effects of microduplications are caused by changes in some critical dose-sensitive genes or in a single gene, but it’s essential the intervention of a duplication that disrupts its integrity. Microduplication syndromes often present a non- clear phenotype and another peculiarity is that they are inherited from apparently normal parents. Since many microduplications are not associated with physical or developmental anomalies, the functional role of genes included with in the copy number variations of speciﬁc chromosome regions requires careful evaluation. Selected dosage-sensitive genes may affect the phenotype by both haploinsufﬁciency and duplication. We report the case of a male pediatric patient with multiple congenital anomalies and mild mental retardation whose genotype was characterized by two microduplication phenomena: the first one involving 16p13.3 region and the second one involving 16q11.2 region, both interesting a non codifying sequence.
The probando, a 6-year-old male, is the ﬁrst child of healthy, nonconsanguineous parents. The mother has had two pregnancies: by the first one our patient was born, while the second one was prematurely interrupted because of fetal heart disease (complete atrioventricular canal).
He was born at the 34th + 6 days of gestation by abortion threats complicated pregnancy. Birth weight was 1, 800 g (under 5th centile), birthlength 42 cm (10th centile) and head circumference 31 cm (between 10th and 25th centile).
At birth, congenital hypotiroidism was diagnosed, so hormone replacement therapy was initiated. A month later, the child underwent a surgical intervention to correct isthmian coarctation of the aorta and interventricular defect), a congenital heart defect formerly diagnosed with fetal echocardiography.
Since the first months of life he was fed with artificial nutrition, mainly through gavage. Psychomotor development was delayed and a severe impairment of both ponderal and statural growth was observed.
Another surgical intervetion was carried out at the age of three because of bilateral inguinal hernia
At the time of our ﬁrst observation, at the age of five years, his speech was limited to few short sentences and impaired because of vocal cord paralysis. He wasn’t autonomous in everyday activities. On neurological exam he had moderate mental retardation and no behavioral problems were observed. He never had had seizures.
Transfontanellar ultrasonography, carried out in the first months of life, didn’t highlight anomalies: the supratentorial ventricular system appears on axis if compared to the midline; morphology and volume limits were also normal like audiological evaluation. No alteration at the eye exam with fundus oculi , except for bilateral strabismus. Urogenital system was free from malformation events.
On laboratory findings hypercalcemia was detected, but other bioumoral parameters weren’t modified.
On physical examination, weight was 11.5 kg (< 3th centile), height 97 cm (- 2 SD) and head circumference 44 cm (< 3th centile). He had a peculiar face appearance characterized by microcephaly, epicanthus , hypertelorism, strabismus, flat nasal root, big low-set ears with left folded lobe. Hands were characterized by bilateral clinodattilia.
Methods and results
Fluorescence in situ hybridization (FISH) for Williams syndrome was negative. Analysis for Kabuki syndrome and chromosome 11 methylation test are both negative.
ArrayCGH documented 2 microduplications, the first one situated in the 16p13.3 region, extended about 80 Kb, and the second one involving 16q11.2 region, externded about 152 Kb. Both microduplication were inherited from patient’s father, who was healthy.
NGS was also performed, but we are still attend the result.
The described patient presents a double microduplication interesting two different regions of chromosome 16.
According to literature case-report and studies, most of duplications phenomena interesting 16p13.3 region, are associated with a peculiar phenotype characterized by mental retardation, delay in weight and height developement, small head circumference, facial anormalities and fingers anomalies, e.g. clinodattilia observed in our probando. How is demonstrate by Digilio et al., phenotypic severity, such as facial dysmorphism and intellectual disability in patients with 16p duplication , could be correlated with the size of the duplicated segment.
Other 16p13.3 duplication cases are also associated with a more severe phenotype, characterized by major malformations, such as cleft palate, congenital heart defects and genitourinary abnormalities, severe psychomotor retardation, growth delay with microcephaly, seizures, and a speciﬁc facial appearance (round head, upslanting and narrow palpebral ﬁssures, sparse eyebrows, broad nasal bridge, rounded nasal tip, , long philtrum, thin upper lip, prominent glabella and micrognathia). 16q11.2 duplication is less frequent, in fact there ore only few studies about it. One of them describes the association with q13 in a 15 week foetus, who presented facial anomalies, mild pyelectasia, minor dysgenesis of the ovaries and an atypical outﬂow of the right arteria thyroidea ima.
All these duplications are much larger than those detected in our patient and they interest the codifying sequence, differently from our case.
Both the microduplication described in our patient can’t be considered as only responsible of the phenotype. They are benign, short, interesting a non codifying sequence and they are also present in his father, who doesn’t present phenotypical alteration or health problems. Although errors in development and phenotypical alteration will not be curable by such strategies, the observed problems in mental function might beneﬁt from therapeutic intervention.
- Marangi G. , Leuzzi V., Orteschi D., Grimaldi M.E. , Lecce R., Neri G., Zollino M., Duplication of the Rubinstein–Taybi Region on 16p13.3 Is Associated With a Distinctive Phenotype, Am J Med Gen Part A 146A:2313–2317 (2008)
- Chen J-L, Yang Y-F, Huang C, Wang J, Yang J-F, Tan Z-P. 2012. Clinical and molecular delineation of 16p13.3 duplication in a patient with congenital heart defect and multiple congenital anomalies. Am J Med Genet Part A 158A:685–688
- Digilio MC, Bernardini L, Capalbo A, Capolino R, Gagliardi MG, Marino B, Novelli A, Dallapiccola B. 2009. 16p subtelomeric duplication: A clinically recognizable syndrome. Eur J Hum Genet 17:1135– 1140.
- Kokalj-Vokac N., Medica I., Zagorac A., Zagradisnik B., Erjavec A., Gregoric A. 2000. A case of insertional translocation resulting in partial trisomy 16p. Ann Genet 43:131–135.
- Martin CL, Waggoner DJ, Wong A, Uhrig S., Roseberry JA. , Hedrick JF., Pack SD., Russell K., Zackai E., Dobyns WB., Ledbetter DH. 2002. ‘‘Molecular rulers’’ for calibrating phenotypic effects of telomere imbalance. J Med Genet 39:734–740.
- Trimborn M., Wegner R.D., T¨onnies H., Sarioglu N., Albig M., Neitzel H., Prenatal diagnosis and molecular cytogenetic characterisation of a small de novo interstitial duplication 16q11.2-q13 , Prenat Diagn 2006; 26: 273–276.
- Thienpont B., Béna F., Breckpot F., Devriendt N.P., Bottani A., Vermeesch J.R., Sau Wai Cheung and Koen Jean-Pierre Fryns, Geert Mortier, Jan M Friedman, Laurent Villard, Gorski, Farah Zahir, Siu Li Yong, Michael M Morris, Stefania Gimelli, Chin-To Fong, Jennifer L Kussmann, Dorothy K Grange, Jerome L Björn Menten, Hilde Van Esch, Emmanuel Scalais, Jessica M Salamone, Duplications of the critical RubinsteineTaybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome, J Med Gen 2010 47: 155-161 originally published online October 14.