Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia.

Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.

Intragenic Deletions in FLNB Are Part of the Mutational Spectrum Causing Spondylocarpotarsal Synostosis Syndrome.

Spondylocarpotarsal synostosis syndrome (SCT) is characterized by vertebral fusions, a disproportionately short stature, and synostosis of carpal and tarsal bones. Pathogenic variants in FLNB, MYH3, and possibly in RFLNA, have been reported to be responsible for this condition. Here, we present two unrelated individuals presenting with features typical of SCT in which Sanger sequencing combined with whole genome sequencing identified novel, homozygous intragenic deletions in FLNB (c.1346-1372_1941+389del and c.3127-353_4223-1836del). Both deletions remove several consecutive exons and are predicted to result in a frameshift. To our knowledge, this is the first time that large structural variants in FLNB have been reported in SCT, and thus our findings add to the classes of variation that can lead to this disorder. These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT.

ncVarDB: a manually curated database for pathogenic non-coding variants and benign controls.

Variants within the non-coding genome are frequently associated with phenotypes in genome-wide association studies. These non-coding regions may be involved in the regulation of gene expression, encode functional non-coding RNAs, or influence splicing and other cellular functions. We have curated a list of characterized non-coding human genome variants based on the published evidence that indicates phenotypic consequences of the variation. In order to minimize annotation errors, two curators have independently verified the supporting evidence for pathogenicity of each non-coding variant in the published literature. The database consists of 721 non-coding variants linked to the published literature describing the evidence of functional consequences. We have also sampled 7228 covariate-matched benign controls, that have a population frequency of over 5%, from the single nucleotide polymorphism database (dbSNP151) database. These were sampled controlling for potential confounding factors such as linkage with pathogenic variants, annotation type (untranslated region, intron, intergenic, etc.) and variant type (substitution or indel). The dataset presented here represents a curated repository, with a potential use for the training or evaluation of algorithms used in the prediction of non-coding variant functionality. Database URL: https://github.com/Gardner-BinfLab/ncVarDB.

Deletion of Exon 1 in AMER1 in Osteopathia Striata with Cranial Sclerosis.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of AMER1, or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in AMER1. Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of AMER1 in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.

Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth.

The family of Tre2-Bub2-Cdc16 (TBC)-domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP-independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss-of-function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B-deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

Building Economic Security Today: making the health-wealth connection in Contra Costa county's maternal and child health programs.

In recent years, maternal and child health professionals have been seeking approaches to integrating the Life Course Perspective and social determinants of health into their work. In this article, we describe how community input, staff feedback, and evidence from the field that the connection between wealth and health should be addressed compelled the Contra Costa Family, Maternal and Child Health (FMCH) Programs Life Course Initiative to launch Building Economic Security Today (BEST). BEST utilizes innovative strategies to reduce inequities in health outcomes for low-income Contra Costa families by improving their financial security and stability. FMCH Programs' Women, Infants, and Children Program (WIC) conducted BEST financial education classes, and its Medically Vulnerable Infant Program (MVIP) instituted BEST financial assessments during public health nurse home visits. Educational and referral resources were also developed and distributed to all clients. The classes at WIC increased clients' awareness of financial issues and confidence that they could improve their financial situations. WIC clients and staff also gained knowledge about financial resources in the community. MVIP's financial assessments offered clients a new and needed perspective on their financial situations, as well as support around the financial and psychological stresses of caring for a child with special health care needs. BEST offered FMCH Programs staff opportunities to engage in non-traditional, cross-sector partnerships, and gain new knowledge and skills to address a pressing social determinant of health. We learned the value of flexible timelines, maintaining a long view for creating change, and challenging the traditional paradigm of maternal and child health.

Integrating the life course perspective into a local maternal and child health program.

For many decades, early access to prenatal care has been considered the gold standard for improving birth outcomes. In Contra Costa County, a diverse urban and suburban county of over one million people in the San Francisco Bay Area, the Family Maternal and Child Health Programs of Contra Costa Health Services (CCHS) have seen high rates of early entry into prenatal care since 2000. Yet despite our best efforts to increase access to quality prenatal care, our rates of low birth weight and infant mortality, especially among African Americans, continue to be high. When we were introduced to the Life Course Perspective in 2003 as an organizational framework for our programmatic activities, we recognized that emerging scientific evidence in the literature demonstrated the importance of social and environmental factors in determining health and health equity, and supported a general impression in the field that prenatal care was not enough to improve birth outcomes. The Life Course Perspective suggests that many of the risk and protective factors that influence health and wellbeing across the lifespan also play an important role in birth outcomes and in health and quality of life beyond the initial years. In this article, we describe the Life Course Perspective and how one local Maternal and Child Health Program adopted and adapted this paradigm by creating and launching a Life Course Initiative to guide our programs and services. The Life Course Initiative implemented by CCHS is designed to reduce inequities in birth outcomes, improve reproductive potential, and change the health of future generations by introducing a longitudinal, integrated, and ecological approach to implementing maternal and child health programs.