Fetal Presentation of MYRF-Related Cardiac Urogenital Syndrome: An Emerging and Challenging Prenatal Diagnosis.

Purpose: MYRF-related cardiac-urogenital syndrome (MYRF-CUGS) is a rare condition associated with heterozygous MYRF variants. The description of MYRF-CUGS phenotype is mostly based on postnatal cases and 36 affected individuals have been published so far. We aim now to delineate the prenatal phenotype of MYRF-CUGS by reporting clinical data from fetuses and neonates with a pathogenic MYRF variant.

Neurodevelopmental and other phenotypes recurrently associated with heterozygous BAZ2B loss-of-function variants.

The bromodomain adjacent to zinc finger 2B (BAZ2B) gene encodes a chromatin remodeling protein that has been shown to perform a variety of regulatory functions. It has been proposed that loss of BAZ2B function is associated with neurodevelopmental phenotypes, and some recurrent structural birth defects and dysmorphic features have been documented among individuals carrying heterozygous loss-of-function BAZ2B variants. However, additional evidence is needed to confirm that these phenotypes are attributable to BAZ2B deficiency.

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H () or SNF2L () ISWI-chromatin remodeling enzyme. Pathogenic variants in and were previously implicated in NDDs.

Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

Background: KBG syndrome is caused by haploinsufficiency of and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined.

Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network.

BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations.

Congenital hydrocephalus: new Mendelian mutations and evidence for oligogenic inheritance.

Background: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

Purpose: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.

Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).

Results: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.

uORF-introducing variants in the 5'UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome.

Cornelia de Lange syndrome (CdLS) is a clinically-recognizable rare developmental disorder. About 70% of patients carry a missense or loss-of-function pathogenic variant in the NIPBL gene. We hypothesized that some variants in the 5'-untranslated region (UTR) of NIPBL may create an upstream open reading frame (uORF), putatively leading to a loss of function.

Implementation of fetal clinical exome sequencing: Comparing prospective and retrospective cohorts.

Purpose: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.

Methods: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.

Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients.

Functional skin barrier requires sphingolipid homeostasis; 3-ketodihydrosphingosine reductase or KDSR is a key enzyme of sphingolipid anabolism catalyzing the reduction of 3-ketodihydrosphingosine to sphinganine. Biallelic mutations in the KDSR gene may cause erythrokeratoderma variabilis et progressive-4, later specified as PERIOPTER syndrome, emphasizing a characteristic periorifical and ptychotropic erythrokeratoderma. We report another patient with compound heterozygous mutations in KDSR, born with generalized harlequin ichthyosis, which progressed into palmoplantar keratoderma.

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.

Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified.

Parental mosaicism in Marfan and Ehlers-Danlos syndromes and related disorders.

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1.

Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition.

BNAR syndrome (MIM608980) is a very rare condition: nine cases belonging to three unrelated families were reported since its first description in 2002. The distinctive clinical feature is the bifidity of the tip of the nose and its association with anorectal and/or renal anomalies. Its molecular basis consisting of biallelic FREM1 missense or nonsense mutations was elucidated after studying the original Egyptian family and was confirmed in two families originating from Afghanistan and Pakistan.

GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome.

Congenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown.