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Background The DSP gene encodes the desmosomal protein desmoplakin and is located on chromosome 6. Pathogenic variants in this gene have been linked to different phenotypes that may include the skin, hair, nails, teeth, and the heart. Lethal acantholytic epidermolysis bullosa (LAEB, OMIM # 609638) is a severe and lethal form of epidermolysis bullosa, caused by biallelic pathogenic variants in the DSP gene. Case presentation This report describes two fetuses from the same family, both affected by LAEB. The parents were second degree cousins. Both fetuses showed multiple sonographic abnormalities antenatally. The first fetus had a lemon shaped skull, an abnormal profile with frontal bossing, flat nasal bridge, nasal hypoplasia and micrognathia. There was increased pericardial fluid, situs ambiguous (left stomach with dextrocardia) and hypoplastic aortic arch. The kidneys were suspected as dysplastic and indeed there was also oligohydramnios. Echogenic sediment was noted in the fetal stomach. The fetus was small for gestational age (SGA) with an estimated fetal weight (EFW) under the 3rd percentile. The second fetus exhibited a novel sonographic sign - constantly open eyelids. Additional notable sonographic signs were echogenic amniotic fluid, and an abnormal profile comprising of flat nasal bridge, hypoplastic nose and micrognathia. Furthermore, hypospadias was suspected as well as abnormal scrotum. The scan revealed echogenic sediment in stomach and SGA fetus with EFW under 3rd percentile similarly to the previous pregnancy. After delivery severe extensive skin and mucosal erosion and sloughing were evident and the neonate succumbed at day 2 of life. Extensive genetic workup diagnosed LAEB in both children. Discussion and conclusions This is the first report to describe the antenatal sonographic phenotype of LAEB. We discuss the diverse phenotypes of DSP gene pathogenic variants and review the specific biochemical and sonographic findings in the context of congenital skin denudation diseases.

PHF20 encodes plant homeodomain finger protein 20 (PHF20), a component of the KAT8‐containing nonspecific lethal (NSL) complex that deposits acetylation on histone H4 to activate gene expression. We report two unrelated individuals with developmental delay, microcephaly, and distinctive facial features, in whom exome sequencing and chromosomal microarray analysis revealed a homozygous deletion of PHF20 that segregated with the disease phenotype in their families. Breakpoint junction sequencing revealed an Alu–Alu ‐mediated deletion event. Western blot in cells from an affected individual showed undetectable PHF20, while levels of other NSL complex subunits were unaltered. Transcriptomic and epigenomic analysis revealed significant downregulation of gene pathways related to cell projection and neuronal development, associated with reduced histone H4K16 acetylation at these genes. In conclusion, our data suggest that homozygous deletion of PHF20 leads to a neurodevelopmental syndrome, potentially through targeted epigenetic dysregulation and altered gene expression essential for neuronal development. Identifying additional families with biallelic PHF20 variants will further delineate the phenotypic spectrum, and molecular studies in neuronal cell lines will be essential for understanding the disease mechanism.

BackgroundAutosomal dominant (AD) inheritance often arises through haploinsufficiency, dominant-negative or gain of function (GoF) effects, while autosomal recessive (AR) inheritance generally results from partial or complete loss of function (LoF). Yet, a subset of genes demonstrates both inheritance patterns. We aimed to curate a list of such ‘AD/AR’ genes and to propose additional candidates.MethodsAD/AR genes were subcategorised based on genotype-phenotype correlations and disease mechanisms. Using bioinformatic analyses, we compared genes with AD, AR and AD/AR inheritance across various metrics, including gnomAD constraint values, exon count, protein length, quaternary structure and gene ontology terms. A machine learning-based metric was used to account for interdependence among features.ResultsPathogenic variants in AD/AR genes can lead to distinct or similar phenotypes, depending on the molecular mechanism. AD/AR genes exhibit unique bioinformatic properties such as intermediate constraint scores, a combination of gene ontology terms, a greater average number of exons and an elevated propensity to form homomeric/heteromeric proteins. We identified homozygous LoF or clinically reported variants in nine genes previously classified as AD only.ConclusionCollectively, the data suggest that AD/AR genes possess distinctive features that likely underpin their dual inheritance modes. We propose nine candidate AD/AR genes and emphasise caution in filtering by inheritance type alone.

Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ2 = 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.

Background 3-Methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an inborn error of leucine catabolism. Tandem mass spectrometry newborn screening (NBS) programs worldwide confirmed 3MCCD to be the most common organic aciduria and a relatively benign disorder with favorable outcome. In addition, several asymptomatic 3MCCD mothers were initially identified following abnormal screening of their healthy babies and were appropriately termed maternal 3MCCD. Methods This is a retrospective study that summarizes all the clinical, biochemical, and genetic data collected by questionnaires of all 3MCCD individuals that were identified by the extended Israeli NBS program since its introduction in 2009 including maternal 3MCCD cases. Results A total of 36 3MCCD subjects were diagnosed within the 50-month study period; 16 were classified primary and 20 maternal cases. Four additional 3MCCD individuals were identified following sibling screening. All maternal 3MCCD cases were asymptomatic except for one mother who manifested childhood hypotonia. Most of the primary 3MCCD individuals were asymptomatic except for two whose condition was also complicated by severe prematurity. Initial dried blood spot (DBS) free carnitine was significantly lower in neonates born to 3MCCD mothers compared with newborns with primary 3MCCD ( p  = 0.0009). Most of the mutations identified in the MCCC1 and MCCC2 genes were missense, five of them were novel. Conclusions Maternal 3MCCD is more common than previously thought and its presence may be initially indicated by low DBS free carnitine levels. Our findings provide additional confirmation of the benign nature of 3MCCD and we suggest to exclude this disorder from NBS programs.