Further delineation of HIDEA syndrome.

Recently, the genetic cause of HIDEA syndrome (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities) was identified as biallelic pathogenic variants in P4HTM, which encodes an atypical member of the prolyl 4-hydroxylases (P4Hs) family of enzymes. We report seven patients from four new families in whom HIDEA was only diagnosed after whole-exome sequencing (WES) revealed novel disease-causing variants in P4HTM. We note the variable phenotypic expressivity of the syndrome except for cognitive impairment/developmental delay, and hypotonia, which seem to be consistent findings. One patient only presented with hypotonia, developmental delay, and abnormal eye movements, which highlights the challenge in diagnosing milder cases with this new syndrome. Other notable features include mild facial dysmorphism, obesity, and brain dysmyelination and atrophy. We conclude that HIDEA is a highly variable syndrome and suspect that a large fraction of patients will be diagnosed via reverse phenotyping after recessive P4HTM variants are identified by agnostic genomic sequencing assays.

Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.

The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.

Common disease-associated gene variants in a Saudi Arabian population.

BACKGROUND: Screening programs for the most prevalent conditions occurring in a country is an evidence-based prevention strategy. The burden of autosomal recessive disease variations in Saudi Arabia is high because of the highly consanguineous population. The optimal solution for estimating the carrier frequency of the most prevalent diseases is carrier screening. OBJECTIVES: Identify the most influential recessive alleles associated with disease in the Saudi population. DESIGN: We used clinical whole-exome sequencing data from an in-house familial database to evaluate the most prevalent genetic variations associated with disease in a Saudi population. SETTINGS: King Abdullah International Medical Research Center (KAIMRC) and King Abdulaziz Medical City. METHODS: Whole exome sequencing data obtained from clinical studies of family members, a cohort of 1314 affected and unaffected individuals, were filtered using the in-house pipeline to extract the most prevalent variant in the dataset. MAIN OUTCOME MEASURES: Most prevalent genetic variations associated with disease in the Saudi population. SAMPLE SIZE: 1314 affected and unaffected individuals. RESULTS: We identified 37 autosomal recessive variants and two heterozygous X-linked variants in 35 genes associated with the most prevalent disorders, which included hematologic (32%), endocrine (21%), metabolic (11%) and immunological (10%) diseases. CONCLUSION: This study provides an update of the most frequently occurring alleles, which support future carrier screening programs. LIMITATIONS: Single center that might represent the different regions but may be biased. In addition, most of the families included in the database are part of the proband's genetic identification for specific phenotypes. CONFLICT OF INTEREST: None.

Clinical presentation of seven patients with Methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase deficiency; MTHFR (MIM 236250) is widely studied with more than 200 reported cases up to our knowledge from pediatrics to adult patients. Clinical presentation of MTHFR deficiency has a wide spectrum and its severity correlates with the degree of the enzyme activity. We report here seven pediatric cases with variable presentations including apnea at early infancy, in addition to hydrocephalus that needed drainage.

Cord blood versus heel-stick sampling for measuring thyroid stimulating hormone for newborn screening of congenital hypothyroidism.

BACKGROUND: Screening for congenital hypothyroidism (CH) using cord blood or heel-stick samples is considered essential for the prevention of long-term complications CH, which include intellectual disability and slow growth. OBJECTIVE: Compare the sensitivity and specificity of cord blood and heel-stick samples for determining thyroid-stimulating hormone (TSH) levels for the detection of CH. DESIGN: Comparative diagnostic accuracy. SETTINGS: Tertiary care center in Riyadh. PATIENTS AND METHODS: The study included all infants who were delivered during the period from May 2011 to May 2013. As part of routine newborn screening, both cord blood and heel-stick samples were collected from each newborn for CH screening by measuring TSH levels. A cord TSH level was considered positive if the concentration of TSH was more than 60 mIU/L and negative if less than 30 mIU/L. Any cord TSH level between 30-60 mIU/L was considered borderline, and free T4 was measured from the same cord sample. The result was considered positive if the free T4 level was below 9 pmol/L. Heel-stick TSH levels more than 20 µU/L were considered positive. All newborns with positive results were recalled and a peripheral venous sample was taken for TSH and free T4 for confirmation. MAIN OUTCOME MEASURES: Sensitivity and specificity, positive and negative predictive values and recall rates. SAMPLE SIZE: 17 729 screened babies. RESULTS: Of 17 729 neonates screened, 7 were diagnosed as having primary CH. All confirmed cases were detected by both cord and heel-stick TSH levels: 88 cord results were positive (sensitivity 100%, specificity 99.6%, with a recall rate of 0.04%) and 305 heel-stick results were positive (sensitivity 100%, specificity 98.3%, with a recall rate of 1.68%). CONCLUSION: Both cord and heel-stick TSH testing detected all cases of CH. Cord testing was superior to heel-stick testing as the recall rate was lower. We think cord TSH testing is preferable when heel-stick is difficult or early discharge is the practice. LIMITATIONS: Retrospective; the timing of newborn screening for TSH sampling was premature. CONFLICT OF INTEREST: None.

Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome in triplets.

We report female triplets with the clinical and biochemical manifestations of hypoparatyroidism-retardation-dysmorphism (HRD) syndrome also known as Sanjad-Sakati syndrome. They were born at 35 weeks gestation after assisted pregnancy (in vitro fertilization). The parents are first degree cousins from Saudi Arabia.