A novel non-recurrent CNV deletion involving TBX4 and leaving TBX2 intact causes congenital alveolar dysplasia.

Congenital alveolar dysplasia (CAD) belongs to rare lethal lung developmental disorders (LLDDs) in neonates, manifesting with acute respiratory failure and pulmonary arterial hypertension refractory to treatment. The majority of CAD cases have been associated with copy-number variant (CNV) deletions at 17q23.1q23.2 or 5p12. Most CNV deletions at 17q23.1q23.2 were recurrent and encompassed two closely located genes, TBX4 and TBX2. In a few CAD cases, intragenic frameshifting deletions or single-nucleotide variants (SNVs) involved TBX4 but not TBX2. Here, we describe a male neonate who died at 27 days of life from acute respiratory failure caused by lung growth arrest along the spectrum of CAD confirmed by histopathological assessment. Trio-based genome sequencing revealed in the proband a novel non-recurrent ~1.07 Mb heterozygous CNV deletion at 17q23.2, encompassing TBX4 that arose de novo on the paternal chromosome. This is the first report of a larger-sized CNV deletion in a CAD patient involving TBX4 and leaving TBX2 intact. Our results, together with previous reports, indicate that perturbations of TBX4, rather than TBX2, cause severe lung phenotypes in humans.

Prenatal Detection of a FOXF1 Deletion in a Fetus with ACDMPV and Hydronephrosis.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by the arrest of fetal lung formation, resulting in neonatal death due to acute respiratory failure and pulmonary arterial hypertension. Heterozygous single-nucleotide variants or copy-number variant (CNV) deletions involving the FOXF1 gene and/or its lung-specific enhancer are found in the vast majority of ACDMPV patients. ACDMPV is often accompanied by extrapulmonary malformations, including the gastrointestinal, cardiac, or genitourinary systems. Thus far, most of the described ACDMPV patients have been diagnosed post mortem, based on histologic evaluation of the lung tissue and/or genetic testing. Here, we report a case of a prenatally detected de novo CNV deletion (~0.74 Mb) involving the FOXF1 gene in a fetus with ACDMPV and hydronephrosis. Since ACDMPV is challenging to detect by ultrasound examination, the more widespread implementation of prenatal genetic testing can facilitate early diagnosis, improve appropriate genetic counselling, and further management.

Molecular Function and Contribution of TBX4 in Development and Disease.

Over the past decade, recognition of the profound impact of the TBX4 (T-box 4) gene, which encodes a member of the evolutionarily conserved family of T-box-containing transcription factors, on respiratory diseases has emerged. The developmental importance of TBX4 is emphasized by the association of TBX4 variants with congenital disorders involving respiratory and skeletal structures; however, the exact role of TBX4 in human development remains incompletely understood. Here, we discuss the developmental, tissue-specific, and pathological TBX4 functions identified through human and animal studies and review the published TBX4 variants resulting in variable disease phenotypes. We also outline future research directions to fill the gaps in our understanding of TBX4 function and of how TBX4 disruption affects development.

Phenotypic spectrum of FGF10-related disorders: a systematic review.

FGF10, as an FGFR2b-specific ligand, plays a crucial role during cell proliferation, multi-organ development, and tissue injury repair. The developmental importance of FGF10 has been emphasized by the identification of FGF10 abnormalities in human congenital disorders affecting different organs and systems. Single-nucleotide variants in FGF10 or FGF10-involving copy-number variant deletions have been reported in families with lacrimo-auriculo-dento-digital syndrome, aplasia of the lacrimal and salivary glands, or lethal lung developmental disorders. Abnormalities involving FGF10 have also been implicated in cleft lip and palate, myopia, or congenital heart disease. However, the exact developmental role of FGF10 and large phenotypic heterogeneity associated with FGF10 disruption remain incompletely understood. Here, we review human and animal studies and summarize the data on FGF10 mechanism of action, expression, multi-organ function, as well as its variants and their usefulness for clinicians and researchers.

Cytogenetic and molecular genotyping in the allotetraploid Festuca pratensis × Lolium perenne hybrids.

BACKGROUND: Species of the Festuca and Lolium genera, as well as intergeneric Festuca × Lolium (Festulolium) hybrids, are valuable fodder and turf grasses for agricultural and amenity purposes worldwide. Festulolium hybrids can merge in their genomes agronomically important characteristics. However, in polyploid plants, especially in allopolyploids, the hybridization of divergent genomes could contribute to various abnormalities, such as variability in chromosome number, structural rearrangements, and/or disorders in inheritance patterns. Here we studied these issues in allotetraploid Festuca pratensis × Lolium perenne hybrids. RESULTS: Cytogenetic procedures, including fluorescent in situ hybridization, genomic in situ hybridization, and molecular markers - inter-simple sequence repeats (ISSR) were exploited. This cytogenetic approach indicated the dynamics in the number and distribution of ribosomal RNA genes and structural rearrangements for both parental genomes (Festuca and Lolium) in hybrid karyotypes. The separate analysis of F. pratensis and L. perenne chromosomes in hybrid plants (F2-F3 generations of F. pratensis × L. perenne) revealed the asymmetrical level of rearrangements. Recognized structural changes were mainly located in the distal part of chromosome arms, and in chromosomes bearing ribosomal DNA, they were more frequently mapped in arms without this sequence. Based on the ISSR markers distribution, we found that the tetrasomic type of inheritance was characteristic for the majority of ISSR loci, but the disomic type was also observed. Nonetheless, no preference in the transmission of either Festuca or Lolium alleles to the following generations of allotetraploid F. pratensis × L. perenne hybrid was observed. CONCLUSION: Our study reports cytogenetic and molecular genotyping of the F. pratensis × L. perenne hybrid and its following F2-F3 progenies. The analysis of 137 allotetraploid F. pratensis × L. perenne hybrids revealed the higher level of recombination in chromosomes derived from F. pratensis genome. The results of ISSR markers indicated a mixed model of inheritance, which may be characteristic for these hybrids.

A Survey of Genetic Variation and Genome Evolution within the Invasive Fallopia Complex.

The knotweed taxa Fallopia japonica, F. sachalinensis and their interspecific hybrid F. × bohemica are some of the most aggressive invaders in Europe and North America and they are serious threats to native biodiversity. At the same time, they constitute a unique model system for the creation of hybrids and studies of the initiation of evolutionary processes. In the presented study, we focused on (i) examining genetic diversity in selected populations of three Fallopia taxa in the invaded (Poland) and native ranges (Japan), (ii) establishing genome size and ploidy levels and (iii) identifying ribosomal DNA (rDNA)-bearing chromosomes in all of the taxa from the invaded range. We found that the genetic diversity within particular taxa was generally low regardless of their geographical origin. A higher level of clonality was observed for the Polish populations compared to the Japanese populations. Our study suggests that the co-occurrence of F. sachalinensis together with the other two taxa in the same stand may be the source of the higher genetic variation within the F. × bohemica hybrid. Some shift towards the contribution of F. japonica alleles was also observed for selected F. × bohemica individuals, which indicates the possibility of producing more advanced generations of F. × bohemica hybrids. All of the F. sachalinensis individuals were hexaploid (2n = 6x = 66; 2C = 6.01 pg), while those of F. japonica were mostly octoploid (2n = 8x = 88; 2C = 8.87 pg) and all of the F. × bohemica plants except one were hexaploid (2n = 6x = 66; 2C = 6.46 pg). Within the chromosome complement of F. japonica, F. sachalinensis and F. × bohemica, the physical mapping of the rDNA loci provided markers for 16, 13 and 10 chromosomes, respectively. In F. × bohemica, a loss of some of rDNA loci was observed, which indicates the occurrence of genome changes in the hybrid.