Genetic Characteristics And Clinical Phenotype Of A Child With Short Stature And Multiple Malformations Due To Loss Of Heterozygosity In Chromosome Fragment 3p25.3p25.2

Background Prevalence of intellectual disablitity(ID)has been estimated to be about2-3%.ID has affected up to 3% of the children in our country.3p-syndrome is a rare disorder resulting from deletions involving the distal end of chromosome 3p.The 3p deletion syndrome is well recognized as a cause for neural developmental and intellectual disabilities.It presented as developmental delay/ID,psychomotal and mental retardation,congenital heart defects,dysmorphic facial features,abnormal muscle tone,and Associated malformations such as congenital heart disease and polydactyly have been reported.Each a novel technological development in the genetics will be able to improve medical level.Chromosomal microarray analysis(CMA)identified the deleted intervals in 3p-syndrome.Different types of DNA microarray platforms has been used for clinical testing included artificial chromosome–based array comparative genomic hybridization,and oligonucleotide plus single-nucleotide polymorphism(SNP)-based arrays that contain both copy-number and SNP only–based arrays.3p syndrome also presented as growth retardation,developmental delay/ID,microcephaly,hypotonia,low birth weight and craniofacial dysmorphisms.scraniofacial dysmorphisms are comprised of Striking eyebrows with variable morphology(full,arched,straight,broad and synophrys),a tubular nose with broad nasal bridge and anteverted nares,bulbous nasal tip,a long philtrum and downturned corners of the mouth and a thin upper lip.Blepharophimosis ptosis,hypotonia,developmental delay,seizures,feeding problems in infancy and retinopathy,self-injury also presented.The hallmarks of the syndrome included developmental delay,growth retardation,and craniofacial manifestations were identfied(Fernandez et al.,2004;Higginbottom et al.,1982;Narahara et al.,1990;Ramer et al.,1989),hearing loss is not a common feature of the syndrome(Angeloni et al.,1999;Benini et al.,1999)were also reported.Distal chromosome 3p deletions presented with various developmental defects.Most of them have a terminal deletion of the 3p.The phenotype of individuals with deletions varies from normal to severe.The categorization of patients help to identify the key genes in 3p syndrome.The breakpoints mapping of chromosome band 3p25 has been reported [Verjaal and De Nef,1978;Garcia Segredo et al.,1981;Witt et al.,1981;Higginbottom et al.,1982;Reifen et al.,1986;Scwyer et al.,1987;Tazelaar et al.,1991;Mowrey et al.,1993;Phipps et al.,1994;Drumheller et al.,1996;Green et al.,2000].Cleft palate,postaxial polydactyly,gastrointestinal anomalies,renal anomalies are less consistent characteristics.Vary genes made it difficult to ascertain the function of individual genes and the genotype–phenotype correlation.In this study,chromosome microarray was performed to diagnose 3p25.3p25.2 loss of heterozygosity(LOH)syndrome in a patient with unknown growth retardation,mental retardation,dyskinesia and multiple malformations,and to analyze its clinical phenotype and molecular genetic characteristics.Objective To investigate the clinical features and genetic characteristics of patients who presented unknown growth retardation,intellectual disablitity and multiple malformations,especially a boy with rare 3p25.3p25.2 LOH syndrome identified by chromosomal microarray analysis(CMA).Methods 40 patients(20males and 20 females,the mean age was 4.5 ± 2.9 years)who presented unknown growth retardation,intellectual disablitity and multiple malformations was enrolled,the clinical data from all 40 patients were collected,Chromosome karyotype and chromosomal microarray analysis were performed.and a 1-year 4 month aged male patient with LOH in Chromosome fragment 3p25.3p25.2identified by chromosomal microarray analysis who has severely dwarf,development delay,special face and multiple malformations were especially analyzed.Results All the 40 patients showed normal karyotype.A total of 12.5%(5/40)patients who presented growth retardation,special face,multiple malformations identified by chromosomal microarray analysis contains 5 CNVs,1 BLM mutation,1 stat1 mutation,1 POLE mutation,1 ufsp2 mutation and 1 3p25.3p25.2 deletion syndrome.A boy diagnosed 3p25.3p25.2 deletion syndrome,aged one-year and 4 month old,presented intrauterine growth retardation,postnatal growth restriction,language retardation and special face,with multiple malformations(small head deformity,micrognathi,long philtrum,low-set and malformed ears),duodenal atresia,bowel malrotation,congenital heart defects,cryptorchidism,denudation of the glans,abnormal muscle tone,feeding difficulties,sleep disorders and hypothyroidism were analyzed.And Chromosomal microarray analysis results demonstrated a 3327 kb heterozygous deletion in3p25.3p25.2.Conclusions 1.More copy number variations can be detected by chromosome microarray analysis in patients with growth retardation,abnormal facial features and multiple deformities than chromosomal karyotype.CMA should recommended to the first choice to the patients with growth retardation,abnormal facial features and multiple deformities.2.The loss of heterozygous of 3327 kb in 3p25.3p25.2 region resulted in the deletion of SETD5,VHL and FANCD2 genes,which led to the clinical phenotype of this child.