BACKGROUNDWolf-Hirschhorn syndrome (WHS) results from the partial deletion of 4p. This study aimed to identify and fine map the chromosome deletion regions of Chinese children with Wolf-Hirschhorn syndrome among the developmental delay/mental retardation (DD/MR) patients.

METHODSWe analyzed the relationship of phenotype and genotype. Inclusion criteria were: moderate to severe DD/MR, no definite perinatal brain injury, and no trauma, toxication, hypoxia, infection of central nervous system; routine karyotyping was normal, no evidence of typical inherited metabolic disorder or specific neurodegenerative disorders from cranial neuro-imaging and blood/urinary metabolic diseases screening; no mutation of FMR1 in male patients, no typical clinical manifestation of Rett syndrome in female patients. Multiplex ligation-dependent probe amplification (MLPA) and Affymetrix genome-wide human SNP array 6.0 assays were applied to accurately define the exact size of subtelomeric aberration region of four WHS patients.

RESULTSAll four WHS patients presented with severe DD, hypotonia and microcephaly, failure to thrive, 3/4 patients with typical facial features and seizures, 2/4 patients with congenital heart defects and cleft lip/palate, 1/4 patients with other malformations. The length of the deletions ranged from 3.3 Mb to 9.8 Mb. Two of four patients had "classic" WHS, 1/4 patients had "mild"-to-"classic" WHS, and 1/4 patients had "mild" WHS.

CONCLUSIONSWHS patients in China appear to be consistent with those previously reported. The prevalence of signs and symptoms, distribution of cases between "mild" and "classic" WHS, and the correlation between length of deletion and severity of disease of these patients were all similar to those of the patients from other populations.

Adolescent ; Child ; Female ; Genotype ; Humans ; Male ; Mutation ; Phenotype ; Polymorphism, Single Nucleotide ; genetics ; Wolf-Hirschhorn Syndrome ; genetics ; pathology

OBJECTIVETo screen for genomic copy number variants (CNVs) in a fetus with cardiac abnormalities and intrauterine growth retardation through single nucleotide polymorphism microarray (SNP array) and karyotyping analysis.

METHODSThe fetus and its parents were subjected to conventional G banding and SNP-array analysis. The results were confirmed with fluorescence in situ hybridization (FISH).

RESULTSG-banding analysis showed that the fetus has a karyotype of 47,XX,+mar. The father has a karyotype of 46,XY,t(4;18) (p15.2q11.2), while the mother showed a normal karyotype. SNP-array detected two microduplications at 18p11.32q11.2 (20.5 Mb) and 4p16.3p15.2 (24.7 Mb) in the fetus. The supernumerary marker chromosome carried by the fetus has derived from the balanced translocation carried by its father. The result was confirmed by FISH.

CONCLUSIONBased on the two microduplications, the fetus was diagnosed as Wolf-Hirschhorn syndrome in conjunction with Edward syndrome. Verification of the origin of the supernumerary marker chromosome by SNP-array has provided a basis for prenatal genetic diagnosis.

Chromosome Banding ; Female ; Genetic Testing ; Humans ; In Situ Hybridization, Fluorescence ; Karyotyping ; Polymorphism, Single Nucleotide ; Pregnancy ; Prenatal Diagnosis ; Trisomy 18 Syndrome ; genetics ; Wolf-Hirschhorn Syndrome ; genetics

OBJECTIVE: To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. METHODS: Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. RESULTS: Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. CONCLUSION The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.
Chromosomes, Human, Pair 4 ; genetics ; Chromosomes, Human, Pair 6 ; genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant ; Karyotyping ; Male ; Pedigree ; Pregnancy ; Prenatal Diagnosis ; Translocation, Genetic ; Wolf-Hirschhorn Syndrome ; genetics

OBJECTIVE: To investigate the clinical features of fetuses with Wolf-Hirschhorn syndrome(WHS) and explore the diagnostic methods and prenatal ultrasound characteristics and provide evidence for prenatal genetic counseling. METHODS: We retrospectively analyzed 5 cases of WHS fetuses diagnosed from March 2016 to February 2020, and analyzed the results of chromosomal karyotype analysis and chromosomal microarray analysis (CMA) of the fetuses. RESULTS: Five cases of WHS were detected by CMA, four cases were detected by karyotype analysis. Prenatal ultrasound revealed 4 abnormalities, of which 3 had intrauterine growth restriction, and only 1 had abnormalities of the maxillofacial region. The sequence of the fragments was 4p16.3p16.1 with a loss of 6.5 Mb, 4p16.3p15.32 with a loss of 15.6 Mb combined with 2p25.3 increased by 906kb, 4p16.3p15.31 with a loss of 20.4 Mb, 4p16.p15.1 with a loss of 35 Mb and 4p16.3p14 with a loss of 37 Mb. CONCLUSION Fetal growth restriction may be one of the early manifestations of WHS. Absence of fetal facial abnormality by prenatal ultrasound screening cannot exclude WHS. Karyotype analysis may miss the diagnosis of WHS, while combined CMA techniques can improve the diagnostic accuracy.
Chromosomes, Human, Pair 4/genetics* ; Female ; Fetal Growth Retardation/genetics* ; Humans ; Karyotyping ; Pregnancy ; Prenatal Diagnosis ; Retrospective Studies ; Wolf-Hirschhorn Syndrome/genetics*

Pericentric inversion of chromosome 4 can give rise to 2 alternate recombinant (rec) chromosomesby duplication or deletion of 4p. The deletion of distal 4p manifests as Wolf-Hirschhorn syndrome (WHS). Here, we report the molecular cytogenetic findings and clinical manifestations observed in an infant with 46,XX,rec(4)dup(4q)inv(4)(p16q31.3)pat. The infant was delivered by Cesarean section at the 33rd week of gestation because pleural effusion and polyhydramnios were detected on ultrasonography. At birth, the infant showed no malformation or dysfunction, except for a preauricular skin tag. Array comparative genomic hybridization analysis of neonatal peripheral blood samples showed a gain of 38 Mb on 4q31.3-qter and a loss of 3 Mb on 4p16.3, and these results were consistent with WHS. At the last follow-up at 8 months of age (corrected age, 6 months), the infant had not achieved complete head control.
*Chromosome Deletion ; *Chromosome Duplication ; *Chromosome Inversion ; *Chromosomes, Human, Pair 4 ; Comparative Genomic Hybridization ; Female ; Gestational Age ; Humans ; Infant ; Pleural Effusion/ultrasonography ; Polyhydramnios/ultrasonography ; Pregnancy ; Wolf-Hirschhorn Syndrome/*genetics

OBJECTIVETo explore the genetic causes for a child with multiple congenital malformations and epilepsy through analysis of copy number variations, and to correlate the genotype with the phenotype.

METHODSG-banding karyotyping was performed on the child and her parents. Single nucleotide polymorphisms array (SNP-array) was used to map the exact chromosomal breakpoints in the proband. The result was validated with fluorescence in situ hybridization (FISH).

RESULTSG banding analysis suggested that the proband had a karyotype of 46,XX,del(4)(p15), while both of his parents had a normal karyotype. SNP-array has identified a hemizygous deletion of 13.3 Mb on chromosome 4p16.3p15.33, which has been implicated in Wolf-Hirschhorn syndrome. FISH assay has confirmed the de novo origin of the deletion, with the karyotype and clinical phenotype of both parents taken into consideration.

CONCLUSIONA case of Wolf-Hirschhorn syndrome has been diagnosed by clinical manifestation and karyotyping analysis. Compared with conventional karyotyping analysis, SNP-array has greater resolution and accuracy, and can provide useful information for genetic counseling.

Chromosome Banding ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Infant, Newborn ; Karyotyping ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide ; Wolf-Hirschhorn Syndrome ; genetics

BACKGROUNDWolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome that is typically caused by a deletion of the distal portion of the short arm of chromosome 4. However, there are few reports about the features of Chinese WHS patients. This study aimed to characterize the clinical and molecular cytogenetic features of Chinese WHS patients using the combination of multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH).

METHODSClinical information was collected from ten patients with WHS. Genomic DNA was extracted from the peripheral blood of the patients. The deletions were analyzed by MLPA and array CGH.

RESULTSAll patients exhibited the core clinical symptoms of WHS, including severe growth delay, a Greek warrior helmet facial appearance, differing degrees of intellectual disability, and epilepsy or electroencephalogram anomalies. The 4p deletions ranged from 2.62 Mb to 17.25 Mb in size and included LETM1, WHSC1, and FGFR3.

CONCLUSIONSThe combined use of MLPA and array CGH is an effective and specific means to diagnose WHS and allows for the precise identification of the breakpoints and sizes of deletions. The deletion of genes in the WHS candidate region is closely correlated with the core WHS phenotype.

Child ; Child, Preschool ; Comparative Genomic Hybridization ; methods ; Female ; Genotype ; Humans ; Infant ; Infant, Newborn ; Male ; Multiplex Polymerase Chain Reaction ; methods ; Phenotype ; Wolf-Hirschhorn Syndrome ; genetics

OBJECTIVETo detect chromosomal imbalance in a fetus with complex congenital heart disease, and to correlate the genotype with the phenotype.

METHODSRoutine G-banding was carried out to analyze the karyotypes of the fetus and its parents, and single nucleotide polymorphisms array (SNP-array) was used for delineating fine genomic aberrations. The detected aberrations were confirmed with multiplex ligation-dependent probe amplification (MLPA).

RESULTSThe fetus and its parents all showed a normal karyotype, while array-SNP has detected a 13.87 Mb duplication at 4p16.3-p15.33 and a 15.65 Mb deletion at 11q23.3-q25 in the fetus. The results were confirmed by the MLPA assay.

CONCLUSIONThe partial trisomy 4p (Wolf-Hirschhorn syndrome) and partial monosomy 11q (Jacobsen syndrome) probably underlie the complex heart defects detected in the fetus. Analysis of the karyotypes of its parents offered no help for the determination of the aberrant type and recurrent risk. Compared with routine karyotype analysis, aberrant regions can be identified with array-SNP with greater resolution and accuracy. This has provided useful information for prenatal diagnosis and genetic counseling.

Adult ; Asian Continental Ancestry Group ; genetics ; China ; Chromosomes, Human, Pair 11 ; genetics ; Chromosomes, Human, Pair 4 ; genetics ; Female ; Fetal Diseases ; diagnosis ; genetics ; Humans ; Jacobsen Distal 11q Deletion Syndrome ; embryology ; genetics ; Male ; Pedigree ; Polymorphism, Single Nucleotide ; Pregnancy ; Prenatal Diagnosis ; Wolf-Hirschhorn Syndrome ; embryology ; genetics

OBJECTIVETo confirm the diagnosis of a Wolf-Hirschhorn syndrome by family study using both cytogenetic and molecular genetic techniques.

METHODG-band karyotyping was performed for all the 6 members in the family. Multiplex ligation-dependent probe amplification (MLPA) was used to detect the chromosome abnormality for the proband, his father and brother. Microarray comparative genomic hybridization (Array-CGH) was carried out to map the exact chromosomal breakpoints for the proband.

RESULTThe proband presented with a typical face, delayed growth and hypotonia in Wolf-Hirschhorn syndrome. His G-band karyotype was 46, XY, der(4)t(4;8) (p16.2; p23.1)pat. MLPA showed 4pter loss and 8pter gain. Array-CGH revealed an XY male with a 3.781 Mb deletion of 4p16.3-p16.2 and a 6.760 Mb duplication of 8p23.3-p23.1. The proband's brother has mental retardation and skeletal abnormalities. His G-band karyotype was 46, XY, der(8)t(4;8)(p16.2;p23.1)pat. MLPA showed 4pter gain and 8pter loss. The proband's father had normal phenotype with a balanced translocation of 46, XY, t(4;8)(p16.2;p23.1)pat. MLPA showed a normal result. The proband's grandfather showed a normal phenotype with a balanced translocation 46, XY, t(4;8)(p16.2;p23.1). The other members in the family showed normal phenotypes with normal karyotypes.

CONCLUSIONThe proband has features of Wolf-Hirschhorn syndrome with partial monosomy 4p and partial trisomy 8p. The proband's brother has a partial trisomy 4p and partial monosomy 8p. The derived chromosomes are inherited from paternal balanced translocation t(4;8)(p16.2;p23.1).

Abnormalities, Multiple ; genetics ; Adult ; Chromosome Deletion ; Chromosomes, Human, Pair 4 ; genetics ; Chromosomes, Human, Pair 8 ; genetics ; Comparative Genomic Hybridization ; Female ; Humans ; Infant ; Karyotyping ; Male ; Multiplex Polymerase Chain Reaction ; methods ; Oligonucleotide Array Sequence Analysis ; Pedigree ; Phenotype ; Translocation, Genetic ; Trisomy ; Wolf-Hirschhorn Syndrome ; diagnosis ; genetics