Robinow syndrome in two siblings from consanguineous parents

A Kurdish family had two children affected with Robinow syndrome. The daughter had short stature, macrocephaly, hypertelorism, hepatosplenomegaly, short forearms and marked vertebral anomalies. Her brother had hypertelorism, hypertrophied alveolar ridges, hepatosplenomegaly, short forearms, rib anomaly and ambiguous genitalia. The karyotype of the affected male sibling showed mosaicism for 45X, 46,X,dicY(q11.22), 47,X,dicY(q11.22),dicY(q11.22).     

Na+-K+-ATPase is not involved in the warming-up phenomenon in generalized myotonia

The initial temporary weakness that occurs in autosomal-recessive generalized myotonia diminishes with repetitive contractions. Physiological understanding of this phenomenon is incomplete. The underlying hypothesis of our study was that the "warming-up" phenomenon relates to the exercise-related activation of Na(+)-K(+)-ATPase. Three patients performed isometric exercise of the brachioradialis muscle on two separate days. Randomly, on one of these days the contraction was preceded by a 30-min infusion of the Na(+)-K(+)-ATPase inhibitor ouabain into the brachial artery of the exercising arm (0.4 mug.min(-1).dl(-1)). Force was measured simultaneously with electrical muscle activity using high-density surface electromyography (HD-sEMG). A transient rapid decline in force occurred after initiation of exercise, accompanied by electrophysiological changes indicating sarcolemmal conduction block. Ouabain infusion did not affect the recovery from transient paresis or the accompanying electromyographic changes, indicating that the warming-up phenomenon in generalized myotonia is not mediated by Na(+)-K(+)-ATPase.     

Optimal discrimination of an Abyssinian cat recessive retinal degeneration: a short electroretinogram protocol is more efficient than a long one

AIM: To determine the diagnostic efficiency of scores in a long protocol ectroretinogram (ERG) for Abyssinian cat slow recessive rod/cone dystrophy. METHODS: Kittens (n = 22) were bred from homozygous,affected and heterozygous normals. Ophthalmoscopy was regularly performed and disease signs noted. Cats (age > or = 8 months, 40 sessions, 1-3 repeats) were dark-adapted overnight, anaesthetized and simultaneous binocular ERG recorded using a long protocol. Conventional a- and b-amplitudes and peak implicit times were measured and b/a ratios calculated, initially only for ERG to the maximum photopic and scotopic stimulus. Principal components factor analysis was applied to various subsets of these scores plus age at testing. RESULTS: Six cats with ophthalmoscopic change were classed as affected. Three cats, one tested three times, were suspect. The rest were considered normal. The first analysis, of 80 eyes and 37 parameters, showed that the first factor was the only effective one. Using it, the groups overlapped 5%, scotopic amplitudes and b/a ratios loaded higher than peak times, the eyes were very similar, and age and photopic b/a ratios loaded poorly. The groups were discriminable with all the data. A second analysis, with eyes averaged and the 20 measures loading over 0.5 on the first factor, showed better group separation on factor I alone. An iterative search with varying data sets found that factor I was optimal, with eight ERG measures to the three brightest scotopic and one brightest photopic response. It produced a large absolute separation and classified the suspects consistently. With b/a ratios on these four ERG also included, 12 parameters gave better separation. CONCLUSION: Twelve scores on four ERG separate affected from normal cats with a wide gap and consistently classify suspects. It may work for earlier ages. Additional data probably adds noise. This combination of optimal scores needs confirmation in new data.     

A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2)

Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.     

Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a severe cholestatic liver disease of early life often requiring liver transplantation. Organ shortage leads to consider living-related liver transplantation. Because of possible partial metabolic defect in heterozygotes, the use of familial donors might be questionable. We therefore evaluated the safety of this procedure, for both donors and recipients. We compared a series of seven parental-children pairs, having participated in the living related liver transplant program for PFIC between 1994 and 2001, with that of a series of seven parental-children pairs, performed for biliary atresia (BA) during the same period. No primary graft dysfunction was observed. There was no difference in the course of transaminases, gamma-glutamyl transpeptidase and bilirubin levels after transplantation in both donor and recipient series. Thirteen recipients and 14 donors are alive and well 3-10 yr post-surgery. One PFIC recipient died nine months post-orthotopic liver transplantation from sepsis. We conclude that PFIC heterozygote status of the donor does not increase the risk of liver dysfunction in either recipients or donors, with a similar course compared with BA recipients and donors.     

Choroby wątroby i nerek w przebiegu ciliopatii

Ciliopathies constitute a group of disorders characterized by cilia abnormalities and an extremely heterogeneous clinical presentation. The liver and kidneys are the most commonly affected organs and the term hepatorenal fibrocystic disorders is used to describe ciliopathies with combined liver and kidney involvement. Liver disorders in ciliopathies can be grouped into three categories: congenital hepatic fibrosis, Caroli's disease and polycystic liver disease. Kidney disorders related to primary cilia abnormalities include autosomal dominant and recessive polycystic kidney diseases and nephronophthisis.     

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome

PurposeRABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.MethodsThrough GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.ResultsWe report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.ConclusionCollectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.     

A novel homozygous PTH1R variant identified through whole-exome sequencing further expands the clinical spectrum of primary failure of tooth eruption in a consanguineous Saudi family

ObjectivesThe present study aimed to identify the genetic cause of non-syndromic primary failure of tooth eruption in a five-generation consanguineous Saudi family using whole-exome sequencing (WES) analysis.DesignThe family pedigree and phenotype were obtained from patient medical records. WES of all four affected family members was performed using the 51Mb SureSelect V4 library kit and then sequenced using the Illumina HiSeq2000 sequencing system. Sequence alignment, variant calling, and the annotation of single nucleotide polymorphisms and indels were performed using standard bioinformatics pipelines. The genotype of candidate variants was confirmed in all available family members by Sanger sequencing.ResultsPedigree analysis suggested that the inheritance was autosomal recessive. WES of all affected individuals identified a novel homozygous variant in exon 8 of the parathyroid hormone 1 receptor gene (PTH1R) (NM_000316: c.611T>A: p.Val204Glu).ConclusionTo the best of our knowledge, this is the first report of primary failure of eruption caused by a homozygous mutation in PTH1R. Our findings prove the application of WES as an efficient molecular diagnostics tool for this rare phenotype and further broaden the clinical spectrum of PTH1R pathogenicity.     

Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing

BackgroundThe extremely high genetic heterogeneity of hearing loss due to diverse group of genes encoding proteins required for development, function, and maintenance of the complex auditory system makes the genetic diagnosis of this disease challenging. Up to now, 121 different genes have been identified for nonsyndromic hearing loss (NSHL), of which 76 genes are responsible for the most common forms of NSHL, autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsAfter excluding mutations in the most common ARNSHL gene, GJB2, by Sanger sequencing, genetic screening for a panel of genes responsible for hereditary hearing impairment performed in 9 individuals with ARNSHL from unrelated Iranian consanguineous pedigrees.ResultsOne compound heterozygote and eight homozygote variants, of which five are novel, were identified: CDH23:p.(Glu1970Lys), and p.(Ala1072Asp), GIPC3:p.(Asn82Ser), and (p.Thr41Lys), MYO7A:p.[Phe456Phe]; p.[Met708Val], and p.(Gly163Arg), TECTA:p.(Leu17Leufs*19), OTOF:c.1392+1G>A, and TRIOBP:p.(Arg1068*). Sanger sequencing confirmed the segregation of the variants with the disease in each family.ConclusionFinding more variants and expanding the spectrum of hearing impairment mutations can increase the diagnostic value of molecular testing in the screening of patients and can improve counseling to minimize the risk of having affected children for at risk couples.