A Complex Intrachromosomal Rearrangement Disrupting IRF6 in a Family with Popliteal Pterygium and Van der Woude Syndromes.

Clefts of the lip and/or palate (CL/P) are considered the most common form of congenital anomalies occurring either in isolation or in association with other clinical features. Van der woude syndrome (VWS) is associated with about 2% of all CL/P cases and is further characterized by having lower lip pits. Popliteal pterygium syndrome (PPS) is a more severe form of VWS, normally characterized by orofacial clefts, lower lip pits, skin webbing, skeletal anomalies and syndactyly of toes and fingers. Both syndromes are inherited in an autosomal dominant manner, usually caused by heterozygous mutations in the Interferon Regulatory Factor 6 (IRF6) gene. Here we report the case of a two-generation family where the index presented with popliteal pterygium syndrome while both the father and sister had clinical features of van der woude syndrome, but without any point mutations detected by re-sequencing of known gene panels or microarray testing. Using whole genome sequencing (WGS) followed by local de novo assembly, we discover and validate a copy-neutral, 429 kb complex intra-chromosomal rearrangement in the long arm of chromosome 1, disrupting the IRF6 gene. This variant is copy-neutral, novel against publicly available databases, and segregates in the family in an autosomal dominant pattern. This finding suggests that missing heritability in rare diseases may be due to complex genomic rearrangements that can be resolved by WGS and de novo assembly, helping deliver answers to patients where no genetic etiology was identified by other means.

A rare case of 1q31.1-q32.1 deletion with congenital heart disease.

Partial deletion of the long arm of chromosome 1 is a rare chromosomal abnormality that is not associated with congenital heart disease (CHD). Here we report a case of 1q31.1-q32.1 deletion with CHD, bicuspid aortic valve, aortic coarctation, and ventricular septal defect, which were successfully managed with surgeries. Since the phenotypes of partial 1q deletion vary for each patient, careful follow-up is required. Learning objective: We report a case of 1q31.1-q32.1 deletion with, bicuspid aortic valve, aortic coarctation, and ventricular septal defect, which were successfully managed with surgeries including Yasui procedure.

t(3;14)(p14.1;q32)/FOXP1-IGH translocation in thyroid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

OBJECTIVES: MALT lymphoma occurs in various organs and has several characteristic genetic aberrations. Thyroid MALT lymphoma has been reported to include t(3;14)(p14.1;q32)/FOXP1-IGH as a specific genetic aberration, but the number of studies is limited. METHOD AND RESULTS: We examined 86 thyroid lymphoma cases using fluorescence in situ hybridization (FISH) for the detection of t(3;14)/FOXP1-IGH in formalin fixed paraffin-embedded tissue (FFPE). Histopathological diagnoses of the analyzed specimen were as follows: thyroid MALT lymphoma (n = 59), DLBCL (n = 23), follicular lymphoma (n = 4), and benign lesions (n = 14) included Hashimoto's thyroiditis (n = 13) and other (n = 1). Of the 100 analyzed cases, thirty-six (36 %) thyroid lymphoma cases were positive for t(3;14)/FOXP1-IGH. Thirty-three (55.9 %) of the 59 MALT lymphoma cases were positive for t(3;14)/FOXP1-IGH. Three (13.0 %) of the 23 DLBCL cases were positive for t(3;14)/FOXP1-IGH. All 4 follicular lymphomas examined were negative for t(3;14)/FOXP1-IGH. None of the benign cases was positive for t(3;14)/FOXP1-IGH, including Hashimoto's thyroiditis (0/13) and benign tissue (0/1). CONCLUSIONS: Our study found that t(3;14)/FOXP1-IGH was frequently found in thyroid MALT lymphoma. A detection of t(3;14)/FOXP1-IGH is extremely useful for the differential diagnosis between primary MALT lymphoma of the thyroid and other thyroid disorders.

A novel mosaic 1q32.1 microduplication identified through Chromosome Microarray Analysis: narrowing the smallest critical region including KDM5B gene found associated with neurodevelopmetal disorders.

Microduplications involving 1q32.1 chromosomal region have been rarely reported in literature. Patients with these microduplications suffer from intellectual disability, developmental delay and a number of dysmorphic features, although no clear karyotype/phenotype correlation has yet been determined. In this case report we describe two monochorionic-diamniotic twins with intellectual disability, abnormality of coordination and dysmorphic features associated with a de novo 280 kb mosaic microduplication of 1q32.1 chromosomal region, identified using a Chromosome Microarray Analysis (CMA) and confirmed by quantitative PCR analysis. The duplicated region encompassed entirely three OMIM genes KDM5B (*605393), KLHL12 (*614522), RABIF (*603417) and involved partially SYT2 (*600104). This unique case report allows to redefine the critical 1q32.1 microduplicated region implicated in the ethiopathogenesis of intellectual disability and developmental delay. Furthermore, it suggests that KDM5B gene can have a pivotal role in the development of neurodevelopmental disorders through its demethylase activity.

Congenital second-degree heart block and total anomalous pulmonary venous return associated with microduplication of 1q32.2.

We report a term female infant with congenital heart block and total anomalous of pulmonary venous return. The results of single nucleotide polymorphism oligonucleotide microarray analysis showed an interstitial duplication of approximately 818 Kb, which involved 11 genes, including the entire LAMB3 gene which is known to associate with cardiac conduction defect. Our report adds to the collective knowledge that the cardiac conduction defect is a clinical feature of chromosome 1q32.2 duplication.

Molecular genetic characterization of a prenatally detected de novo interstitial deletion of chromosome 2q (2q31.1-q32.1) encompassing HOXD13, ZNF385B and ZNF804A associated with syndactyly and increased first-trimester nuchal translucency.

OBJECTIVE: We present prenatal diagnosis and molecular genetic characterization of a de novo interstitial deletion of 2q (2q31.1-q32.1) and discuss the genotype-phenotype correlation. CASE REPORT: A 34-year-old, primigravid woman was referred to the hospital at 20 weeks of gestation for genetic counseling because of a prenatally detected de novo interstitial deletion of chromosome 2q (2q31.1-q32.1). She underwent amniocentesis at 17 weeks of gestation because of advanced maternal age and an increased first-trimester nuchal translucency (NT) thickness of 3.6 mm. Amniocentesis revealed a karyotype of 46,XY. However, array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniotic fluid and amniocytes revealed a 13.29-Mb deletion at chromosome 2q31.3-q32.1. The parents did not have such a deletion. Prenatal ultrasound findings were unremarkable. After counseling of the genotype-phenotype correlation of such a chromosome aberration with congenital malformations, the parents elected to terminate the pregnancy. The fetus postnataly manifested hypertelorism and syndactyly of the second and third toes of bilateral feet. Cytogenetic analysis of the umbilical cord revealed a karyotype of 46,XY,del(2)(q31q32). aCGH analysis on the DNA extracted from the cord blood confirmed a 13.35-Mb deletion of 2q31.1-q32.1 encompassing HOXD13, ZNF385B, ITGA4, CERKL, PDE1A, FRZB and ZNF804A. Polymorphic DNA marker analysis revealed a paternal origin of the deletion. CONCLUSION: Fetuses with an interstitial deletion of 2q31.1-q32.1 may be associated with increased first-trimester NT. Haploinsufficiency of HOXD13 is associated with syndactyly. Genomic microarray is useful in detecting subtle chromosomal abnormalities in fetuses with increased NT and normal karyotype.

De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus.

BACKGROUND: Van der Woude syndrome is the most common among syndromes which include cleft lip and/or cleft palate as one of the presentations. It is usually caused by mutations in the interferon regulatory factor 6 (IRF6) gene. CASE PRESENTATION: We previously reported on a patient with suspected deletion of the IRF6 gene. Using the Affymetrix Human SNP 6.0 Array, the interstitial deletion has been confirmed and found to be approximately 2.327-2.334 Mb within the 1q32.2 region. Although several known genes were deleted, the patient has no other phenotype apart from the orofacial presentations typical of VWS. The same deletion was not present in either parent and his two siblings were also phenotypically normal. CONCLUSIONS: Other than IRF6, the genes which are deleted in this patient appear to be insensitive to copy number and haploinsufficiency. We compared the deletion in this patient with another case which was also mapped by high resolution array but had additional phenotypic features.