Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.     

Severe facial clefting,limbic dermoid,hypoplasia of the corpus callosum,and multiple skin appendages: Severe frontofacionasal “dysplasia” or newly recognised syndrome?

We report on a child with severe midline facial cleft, bilateral cleft lip and palate, telecanthus, S-shaped palpebral fissures, limbic dermoid, midface hypoplasia, hypoplastic corpus callosum, and multiple skin appendages. This case may be an example of severe frontofacionasal “dysplasia” or a newly recognised syndrome. © 1996 Wiley-Liss, Inc.     

Autosomal recessive micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis.

The clinical courses, neuroimaging and muscle biopsy findings of two infants born to an inbred Arab family are described. They had a syndrome of micrencephaly with simplified gyral pattern, abnormal myelin formation and arthrogryposis. Increased variation of fiber size was seen in the muscle biopsy, creatine kinase, however was normal. Large areas of muscle were replaced by adipofibrous tissue. The infants had dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. The abnormalities were suggestive of microlissencephaly probably associated with a dysgenetic process in the muscles. The syndrome showed an autosomal recessive inheritance.     

A syndrome of immune complex glomerulonephritis and ophthalmic abnormalities

Two sibs (one male and one female) suffering from a combination of immune complex glomerulonephritis and various ophthalmologic disorders are presented. The two cases belong to a family in which the parents are not related and seven sibs are affected, three females and a male with the combination, and three males with severe ophthalmological changes and proteinuria. Clinically, case 2 had only ophthalmological manifestations but renal biopsy findings were similar to those of case 1, which could mean that all the others with eye abnormalities also had renal disease. Although there are several reports of combinations of eye and renal disorders, the sibs reported here do not fit into any of the known syndromes.     

A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22

Introduction: Previously, autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT [1]) was mapped to chromosome 1q42–43 with identification of pathogenic mutations in RYR2. Autosomal recessive CPVT (2) was mapped to chromosome 1p13–21, leading to the identification of mutations in CASQ2. In this study, we aimed to elucidate clinical phenotypes of a new variant of CPVT (3) in an inbred Arab family and also delineate the chromosomal location of the gene causing CPVT (3).
Methods and Results: In a highly inbred family, clinical symptoms of CPVT appeared early in childhood (7–12 years) and in three of the four cases, the first appearance of symptoms turned into a fatal outcome. Parents of the affected children were first-degree cousins and without any symptoms. Segregation analysis suggested an autosomal recessive inheritance. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 25-Mb interval on chromosome 7p14-p22. A maximal multipoint LOD score of 3.17 was obtained at marker D7S493. Sequencing of putative candidate genes, SP4 , NPY , FKBP9 , FKBP14 , PDE1C , and TBX20 , in and around this locus, did not reveal any mutation.
Conclusions: We have identified a novel highly malignant autosomal recessive form of CPVT and mapped this disorder to a 25-Mb interval on chromosome 7p14-p22.     

Radiological manifestations of the skeleton, lungs and brain in Stueve-Wiedemann syndrome

A total of 25 patients with the rare skeletal dysplasia Stueve-Wiedemann syndrome (SWS) have been evaluated during the last 11 years. Of all patients with clinical suspicion of SWS, skeletal and chest radiographs were obtained for classification of the underlying skeletal dysplasia. In one case, CT was carried out for the first time for further investigation of the midface hypoplasia. Typical conventional radiological findings and CT features were analysed and compared with published data. Early diagnosis of SWS was made by correlating radiological and clinical findings. Follow-up radiological examinations of the skeleton and of the chest were carried out in six children surviving infancy for evaluation of progression. Clinically, they suffered from progressive orthopaedic problems, recurrent aspiration pneumonia and recurrent episodes of hyperthermia, as well as cutaneous infections. Radiologically progressive bowing of the long tubular bones and progressive metaphyseal decalcification were present on follow-up skeletal radiographs. Skeletal abnormalities in SWS are so characteristic that an early post-partum diagnosis can be made by correlation of typical clinical and radiological findings. Few cases survive infancy. First, these patients face progressive orthopaedic problems and respiratory infections.     

Mutations in the human laminin β2 (LAMB2) gene and the associated phenotypic spectruma

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease‐causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N‐terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist. Hum Mutat 31:992–1002, 2010. © 2010 Wiley‐Liss, Inc.     

A study of possible deleterious effects of consanguinity

The aim of the study was to determine whether consanguineous marriages result in reproductive wastage and an increased incidence of illness in the offspring in a community with a long history of inbreeding and an expected high rate of consanguineous marriage. A representative sample of 2200 women aged > 15 years from Dubai and Al Ain, two cities in the United Arab Emirates, representing on the one hand a modern metropolis and on the other a traditional society, were studied. A questionnaire, which included questions on age, parity, gravidity, number of stillbirths, number of abortions, number of children alive, neonatal deaths and specific illnesses in children, was administered by nurses in antenatal and gynaecological clinics in the two cities. The rate of consanguineous marriage was 50.5% and parity, gravidity, ages and number of children were similar in consanguineous and non-consanguineous groups. There was no significant difference in rates of abortion, stillbirth and neonatal death between the two groups. Overall, there was statistically significant higher reproductive wastage in consanguineous couples, but when the category of less than second cousins was excluded from the consanguineous group no difference was found in reproductive wastage between consanguineous and non-consanguineous marriages. Children born to consanguineous unions also had significantly higher incidences of illnesses (37.1%) than those of non-consanguineous unions (29%). The occurrence of malignancies, congenital abnormalities, mental retardation and physical handicap was significantly higher in offspring of consanguineous than non-consanguineous marriages. In conclusion, consanguinity did not result in reproductive wastage, but was found to be an important factor in the causation of specific illnesses in offspring.