Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.

Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males.

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity.

The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here?

Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity.

Expanding the genetic landscape of oral-facial-digital syndrome with two novel genes.

Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis.

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS.

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth.

Our objective was to further expand the spectrum of clinical characteristics of the deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood.

mutations in the X-linked gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features.

Introduction: Pigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko's lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 () have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.

Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy.

Background: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also known as Wolman disease. We sought to determine the outcomes and clinical needs of infants diagnosed with LAL-D, treated with enzyme replacement therapy (ERT).

Methods: A chart review was conducted on two infantile-onset LAL-D patients to determine clinical outcomes based on laboratory results, abdominal imaging, growth and dietary records, cardiology, endocrinology, ophthalmology, hematology, and neurocognitive evaluations.

A Case of Reversible Infantile Respiratory Chain Deficiency Presenting With Hypotonia, Hyperammonemia, and Failure to Thrive.

Reversible infantile respiratory chain deficiency, previously termed reversible infantile cytochrome c oxidase (COX) deficiency myopathy, is a rare mitochondrial disorder that is characterized by severe hypotonia and generalized muscle weakness in infancy that is associated with lactic acidosis. Affected infants will spontaneously recover, if they survive the first months of life. Here, we present the case of a 4-week-old girl who initially presented with hyperammonemia, hypotonia, and failure to thrive, for which she was referred for genetic evaluation.

De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects.

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads.

encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of encephalopathy and explored potential prospects of personalised medicine.

Methods: Data of 48 individuals with de novo variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.

Diagnostic Yield of Epilepsy Panels in Children With Medication-Refractory Epilepsy.

Background: When no chromosomal variations are identified, patients with suspected genetic etiologies can be tested using next-generation sequencing utilizing epilepsy panels. The primary objective of this study was to analyze the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects with non-clinically significant comparative genomic hybridization microarray results.

Methods: We completed a single-center retrospective review of the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects aged 18 years or less who had non-clinically significant comparative genomic hybridization microarray results from January 2011 to December 2014.

Atypical GH insensitivity syndrome and severe insulin-like growth factor-I deficiency resulting from compound heterozygous mutations of the GH receptor, including a novel frameshift mutation affecting the intracellular domain.

Background/aims: GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding protein (GHBP), but clinical evidence of GH insensitivity.

Method: Serum and DNA samples from the proband and his parents were analyzed.

Glutaric aciduria type II and narcolepsy in pregnancy.

Background: Glutaric aciduria type II is a rare disorder affecting the metabolism of fatty acid oxidation and several mitochondrial dehydrogenase enzymes. Narcolepsy and cataplexy is a disorder affecting sleep cycles and rapid eye movement activity. There is little information on outcome or management for either disorder in pregnancy.

Biotinidase deficiency: novel mutations and their biochemical and clinical correlates.

Biotinidase deficiency is a defect in the recycling of the vitamin biotin. Biotin supplementation can markedly improve the neurological and cutaneous symptoms of affected children and prevent symptoms in children identified by newborn screening or treated since birth. We have determined thirteen novel mutations in children with the disorder.