Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2.

CTNND2 encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript.

Different MAPT haplotypes influence expression of total MAPT in postmortem brain tissue.

The MAPT gene, encoding the microtubule-associated protein tau on chromosome 17q21.31, is result of an inversion polymorphism, leading to two allelic variants (H1 and H2). Homozygosity for the more common haplotype H1 is associated with an increased risk for several tauopathies, but also for the synucleinopathy Parkinson's disease (PD).

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus.

Expanding the phenotype of 12q21 deletions: A role of BTG1 in speech development?

We report on a female individual with feeding difficulties, constipation, poor overall growth, periventricular lesions resembling gliosis in brain MRI, recurrent otitis media with palsy of facial nerve, distinct facial features, and pronounced delay in speech development. The latter was the most prominent feature. Molecular karyotyping revealed a heterozygous de novo deletion of 4.

Microdeletions at 19p13.11p12 in five individuals with neurodevelopmental delay.

Only few copy number variants at chromosome 19p13.11 have been reported, thus associated clinical information is scarce. Proximal to these copy number losses, we now identified deletions in five unrelated individuals with neurodevelopmental disorders.

Generation of a homozygous and a heterozygous SNCA gene knockout human-induced pluripotent stem cell line by CRISPR/Cas9 mediated allele-specific tuning of SNCA expression.

Aggregation of alpha-synuclein (aSyn) is closely linked to Parkinson's disease, probably due to the loss of physiological functions and/or gain of toxic functions of aggregated aSyn. Significant efforts have been made elucidating the physiological structure and function of aSyn, however, with limited success thus far in human-derived cells, partly because of restricted resources. Here, we developed two human-induced pluripotent stem cell lines using CRISPR/Cas9-mediated allele-specific frame-shift deletion of the aSyn encoding gene SNCA, resulting in homo- and heterozygous SNCA knockout.

SRD5A3-CDG: Twins with an intragenic tandem duplication.

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare metabolic disease mainly characterized by psychomotor disability, visual impairment, and variable eye malformations caused by bi-allelic pathogenic variants in SRD5A3. So far, only 23 distinct mutations were described. Exome sequencing in 32-year old monozygotic male twins revealed only the heterozygous splice variant c.

BDV Syndrome: An Emerging Syndrome With Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome.

Context: CPE encodes carboxypeptidase E, an enzyme that converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, 4 individuals from 2 families with core clinical features including morbid obesity, neurodevelopmental delay, and hypogonadotropic hypogonadism, harboring biallelic loss-of-function (LoF) CPE variants, have been reported.

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants.

7q31.2q31.31 deletion downstream of FOXP2 segregating in a family with speech and language disorder.

Chromosomal 7q31 deletions have been described in individuals with variable neurodevelopmental phenotypes including speech and language impairment. These copy number variants usually encompass FOXP2, haploinsufficiency of which represents a widely acknowledged cause for specific speech and language disorders. By chromosomal microarray analysis we identified a 4.

CRISPR/Cas9 mediated generation of human ARID1B heterozygous knockout hESC lines to model Coffin-Siris syndrome.

ARID1B haploinsufficiency induced by missense or nonsense mutations of ARID1B is a cause of Coffin-Siris syndrome (CSS), a neurodevelopmental disorder associated with intellectual disability. At present, no appropriate human stem cell model for ARID1B-associated CSS has been reported. Here, we describe the generation and validation of ARID1B hESCs by introducing out of frame deletions into exon 5 or 6 of ARID1B with CRISPR/Cas9 genome editing.

Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Objective: 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies.

Methods: Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes.

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features.

The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy.

Background: The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.

Results: In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing.

A biallelic truncating AEBP1 variant causes connective tissue disorder in two siblings.

Biallelic variants in the AEBP1 gene cause a novel autosomal-recessive connective tissue disorder (CTD) reminiscent of Ehlers-Danlos Syndrome (EDS). The four previously reported individuals show considerable clinical variability. Unbiased high-throughput sequencing enables the rapid identification of additional cases for such rare entities.

Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium.

Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines.

α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies.

α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear.

Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment.

Non-recurrent deletions in 2q24.1, minimally overlapping two genes, NR4A2 and GPD2, were recently described in individuals with language impairment and behavioral and cognitive symptoms. We herewith report on a female patient with a similar phenotype of severe language and mild cognitive impairment, in whom we identified a de novo deletion covering only NR4A2.

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.

Importance: Autosomal recessive inherited neurodevelopmental disorders are highly heterogeneous, and many, possibly most, of the disease genes are still unknown.

Objectives: To promote the identification of disease genes through confirmation of previously described genes and presentation of novel candidates and provide an overview of the diagnostic yield of exome sequencing in consanguineous families.

Design, Setting, And Participants: Autozygosity mapping in families and exome sequencing of index patients were performed in 152 consanguineous families (the parents descended from a same ancestor) with at least 1 offspring with intellectual disability (ID).

Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2.

Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high- and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor.

FOXP2 variants in 14 individuals with developmental speech and language disorders broaden the mutational and clinical spectrum.

Background: Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families.