Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay.

Malay Version of Nijmegen Cochlear Implant Questionnaire and Quality of Life of Patients with Post-lingual Deafness.

Objective: The Nijmegen Cochlear Implant questionnaire (NCIQ) was used to gauge the quality of life (QOL) improvement among cochlear implant (CI) users who suffered from post-lingual deafness. This study aimed to determine the consistency and reliability of the Malay version of the Nijmegen Cochlear Implant questionnaire (NCIQ-M) and to report the QOL of patients using NCIQ-M.

Methods: This study has two phases: Phase I involves the translation of the NCIQ from English to Malay, followed by internal consistency and test-retest reliability assessment of the final version of NCIQ-M.

Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+).

Background: Nicotinamide adenine dinucleotide (NAD+) depletion is associated with numerous diseases in humans. Recently it was revealed that genetic blockage of the NAD+ synthesis pathway in humans causes birth defects in multiple organ systems and miscarriage. Additionally, mice with NAD+ deficiency created through dietary restriction of tryptophan and vitamin B3 were shown to have congenital anomalies affecting virtually every organ system along with miscarriage.

Autosomal recessive LRP1-related syndrome featuring cardiopulmonary dysfunction, bone dysmorphology, and corneal clouding.

We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.

Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3.

Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6.

While inherited hemizygous variants in PHF6 cause X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS) in males, de novo heterozygous variants in females are associated with an overlapping but distinct phenotype, including moderate to severe intellectual disability, characteristic facial dysmorphism, dental, finger and toe anomalies, and linear skin pigmentation. By personal communication with colleagues, we assembled 11 additional females with BFLS due to variants in PHF6. We confirm the distinct phenotype to include variable intellectual disability, recognizable facial dysmorphism and other anomalies.

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy.

Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations.

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously.

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.

Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.

Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities.

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency.

Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously.

The Incidence of Nasopharyngeal Carcinoma in Pahang State of Malaysia from 2012 to 2017.

Background: Nasopharyngeal carcinoma (NPC) is the fifth most common cancer among Malaysians. While several studies have reported the trend of NPC in other states in Malaysia, no studies have reported the trend of NPC in Pahang state. This study was designed to report the number and distribution of newly diagnosed NPC cases in Pahang.

Two cases of different genetic variants of alveolar capillary dysplasia associated with left-sided obstructive CHDs.

Alveolar capillary dysplasia with misalignment of the pulmonary veins is an uncommon disorder that affects the lung vasculature development in the neonatal period and leads to pulmonary hypertension. We describe two patients with alveolar capillary dysplasia associated with left-sided obstructive heart defects with two different genetic variants. Our cases highlight the importance of early recognition of this disease in the setting of persistent and supra-systemic pulmonary hypertension despite surgical correction of the associated lesions.

Nanomechanical Measurement of the Brownian Force Noise in a Viscous Liquid.

We study the frequency spectrum of the thermal force giving rise to Brownian motion of a nanomechanical beam resonator in a viscous liquid. In the first set of experiments, we measure the power spectral density (PSD) of the position fluctuations of the resonator around its fundamental mode at its center. Then, we measure the frequency-dependent linear response of the resonator, again at its center, by driving it with a harmonic force that couples well to the fundamental mode.

SLC6A1 G443D associated with developmental delay and epilepsy.

is associated with an autosomal dominant early-onset seizure and epileptic encephalopathy associated with intellectual disability. We present a 2-yr-old girl with developmental delay and epilepsy, using a new computational filtering impact score to show the patient's variant ranks with other pathogenic variants. Genomic studies within the patient revealed a variant of uncertain significance.

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.

Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone-rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018.

HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals.

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome.

Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34.

The wobble position in the anticodon loop of transfer ribonucleic acid (tRNA) is subject to numerous posttranscriptional modifications. In particular, thiolation of the wobble uridine has been shown to play an important role in codon-anticodon interactions. This modification is catalyzed by a highly conserved CTU1/CTU2 complex, disruption of which has been shown to cause abnormal phenotypes in yeast, worms, and plants.