Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature.

CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders.

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release.

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated.

Genetic evaluation including exome sequencing of two patients with Gomez-Lopez-Hernandez syndrome: Case reports and review of the literature.

Rhombencephalosynapsis (RES) is a rare congenital anomaly of the hindbrain characterized by fusion of the cerebellar hemispheres, cerebellar peduncles, and dentate nuclei with vermian absence or hypogenesis. This anomaly can be isolated or part of a larger spectrum of cerebral abnormalities. At least 90 cases are described in the literature and it has been associated with VACTERL and Gomez-Lopez-Hernandez syndrome (GLHS).

Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress.

Therapeutic Benefit of Blood Transfusion in a Patient With Novel PGK1 Mutation (c.461T>C [p.L154P]).

Phosphoglycerate kinase (PGK) is glycolytic enzyme critical in the creation of adenosine triphosphate. Mutations in the gene for this enzyme, PGK1, are associated with PGK deficiency, which is characterized by neurologic symptoms, nonhereditary spherocytic hemolytic anemia, and myopathy. We present a 20-year-old male with a novel c.

A retrospective review of multiple findings in diagnostic exome sequencing: half are distinct and half are overlapping diagnoses.

Purpose: We evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF).

Methods: Results of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated.

Congenital lumbar hernia-A feature of diabetic embryopathy?

Congenital lumbar hernia is a rare anomaly consisting of protrusion of abdominal organs or extraperitoneal tissue through a defect in the lateral abdominal wall. The majority of affected patients have additional anomalies in a pattern described as the lumbocostovertebral syndrome. We report four patients born to mothers with poorly controlled diabetes with congenital lumbar hernia.

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients.

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations.

38th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2017 Annual Meeting.

The 38th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on August 26th - 29th, 2017 at the Stoweflake Resort and Conference Center in Stowe, VT. The Workshop, which honors the legacy of David W Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis.

A Homozygous RET K666N Genotype With an MEN2A Phenotype.

Context: Germline RET K666N mutation has been described as a pathogenic mutation with low disease penetrance for medullary thyroid cancer (MTC) without other features of multiple endocrine neoplasia type 2A. We describe a patient with homozygous RET K666N mutation with MTC and bilateral pheochromocytoma (PHEO).

Case Description: A 59-year-old woman received a diagnosis of MTC after biopsy of two thyroid nodules.

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families.

Intestinal malrotation in Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome which may include malformations of the central nervous system, heart, genitourinary tract, and other organs. However, intestinal malrotation has not been previously known to be associated with RSTS. This report documents six persons with RSTS who also had malrotation of the intestine requiring surgical repair.

De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome.

Ablepharon macrostomia syndrome: A distinct genetic entity clinically related to the group of FRAS-FREM complex disorders.

Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners.

Investigation of NRXN1 deletions: clinical and molecular characterization.

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization.