ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction.

Autoimmune Disease, Multisystem, with Facial Dysmorphism (ADMFD) is an autosomal recessive disorder due to pathogenic variants in the gene. It is characterized by failure to thrive, dysmorphic facial features, developmental delay, and systemic autoimmunity that can manifest variably with autoimmune hepatitis, thyroiditis, and enteropathy, among other organ manifestations. It was originally described in 10 consanguineous Old Order Amish patients, and more recently in two patients of White British and Black German ethnicities.

Deletion of conserved non-coding sequences downstream from NKX2-1: A novel disease-causing mechanism for benign hereditary chorea.

Background: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role.

Methods And Results: By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants.

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.

Background: has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in were reported recently.

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS.

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698).

De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities.

PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined.

Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients.

The "blepharophimosis-mental retardation" syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge.

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.

Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts.

Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive.

GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.

De Novo Truncating Variants in SON Cause Intellectual Disability, Congenital Malformations, and Failure to Thrive.

SON is a key component of the spliceosomal complex and a critical mediator of constitutive and alternative splicing. Additionally, SON has been shown to influence cell-cycle progression, genomic integrity, and maintenance of pluripotency in stem cell populations. The clear functional relevance of SON in coordinating essential cellular processes and its presence in diverse human tissues suggests that intact SON might be crucial for normal growth and development.

Respiratory motile cilia dysfunction in a patient with cranioectodermal dysplasia.

Ciliopathies such as cranioectodermal dysplasia, Sensenbrenner syndrome, short-rib polydactyly, and Jeune syndrome are associated with respiratory complications arising from rib cage dysplasia. While such ciliopathies have been demonstrated to involve primary cilia defects, we show motile cilia dysfunction in the airway of a patient diagnosed with cranioectodermal dysplasia. While this patient had mild thoracic dystrophy not requiring surgical treatment, there was nevertheless newborn respiratory distress, restrictive airway disease with possible obstructive airway involvement, repeated respiratory infections, and atelectasis.

Craniofacial abnormalities and developmental delay in two families with overlapping 22q12.1 microdeletions involving the MN1 gene.

Deletions spanning the MN1 gene (22q12.1) have recently been proposed as playing a role in craniofacial abnormalities that include cleft palate, as mouse studies have demonstrated that Mn1 haploinsufficiency results in skull abnormalities and secondary cleft palate. We report on four patients (two families) with craniofacial abnormalities and intellectual disability with overlapping microdeletions that span the MN1 gene.

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.

Co-existence of 9p deletion and Silver-Russell syndromes in a patient with maternally inherited cryptic complex chromosome rearrangement involving chromosomes 4, 9, and 11.

We report a patient with a maternally inherited unbalanced complex chromosomal rearrangement (CCR) involving chromosomes 4, 9, and 11 detected by microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). This patient presents with clinical features of 9p deletion syndrome and Silver-Russell syndrome (SRS). Chromosome analysis performed in 2000 showed what appeared to be a simple terminal deletion of chromosome 9p22.

Phenotypic heterogeneity of genomic disorders and rare copy-number variants.

Background: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.

Methods: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.

Subtelomeric deletion of chromosome 10p15.3: clinical findings and molecular cytogenetic characterization.

We describe 19 unrelated individuals with submicroscopic deletions involving 10p15.3 characterized by chromosomal microarray (CMA). Interestingly, to our knowledge, only two individuals with isolated, submicroscopic 10p15.

High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44.

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization.