Clinical and Molecular Update on the Fourth Reported Family with Hamamy Syndrome

We report on 2 cousins, a girl and a boy, born to first-cousin Lebanese parents with Hamamy syndrome, exhibiting developmental delay, intellectual disability, severe telecanthus, abnormal ears, dentinogenesis imperfecta, and bone fragility. Whole-exome sequencing studies performed on the 2 affected individuals and one obligate carrier revealed the presence of a homozygous c.503G&#x3e;A (p.Arg168His) missense mutation in <i>IRX5</i> in both sibs, not reported in any other family. Review of the literature and differential diagnoses are discussed.

Living Kidney Donation in a Type 1 Dent’s Disease Patient from His Mother

Introduction: Dent’s disease is a rare X-linked recessive disorder that manifests in childhood or early adulthood and can lead to end-stage renal disease (ESRD). It occurs in males, who are hemizygous. In patients who develop ESRD, a deceased donor kidney transplant cures the disease. Females are obligate carriers of the mutated gene, and some show a mild Dent’s disease phenotype. There may be reason for concern when considering a female obligate carrier (i.e., the mother) for kidney donation because of the risk of kidney function deterioration. Case Presentation: We describe the first successful kidney transplantation involving a patient with type 1 Dent’s disease and ESRD given a kidney by an obligate carrier of the gene mutation, his mother. Conclusions: After careful assessment of the female obligate carriers, intrafamilial kidney donation in Dent’s disease type 1 is feasible. No deteriorating renal function in the donor was observed.

A challenging chat

At some stage or other, most haemophilia nurses will be faced with the pregnancy of an obligate carrier. As Trish Bell recounts, this can make for a difficult conversation and sleepless nights.

RPS29 is Mutated in a Multi-Case Diamond Blackfan Anemia Family

Abstract 511 Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterized by red blood cell aplasia, variable physical anomalies, and increased risk of leukemia, myelodysplastic syndrome, lymphoma, and certain solid tumors, including osteosarcoma. DBA has been considered to be a disorder of ribosomal biogenesis because approximately 50% of cases are due to a mutation or deletion in 1 of 9 ribosomal protein genes (RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, or RPS26). However, mutations in GATA1, a hematopoietic transcription factor, have recently been reported to also cause DBA. DBA is inherited in an autosomal dominant manner, but de novo germline mutations have also been reported. Our IBMFS cohort study conducts detailed clinical evaluations and medical record review of patients with DBA and their family members. We evaluated a large family with DBA in which mutation testing for the 10 known genes was negative. The male proband had steroid-responsive anemia as a child; he was in remission until he was treated with chemotherapy for squamous cell lung cancer at age 55 years. His healthy sister is an obligate carrier because her daughter was diagnosed with DBA as a child; her daughter had steroid-responsive anemia. The proband's maternal 1st cousin had steroid-responsive DBA as a child which relapsed during pregnancy. Her 3 children (the proband's 2nd cousins) had DBA. One died due to complications of transfusion-related iron overload, one had successful hematopoietic stem cell transplantation for steroid-refractory and transfusion-dependent anemia at age 26 years, and one has been off treatment and in remission for over 20 years. Except for the proband with lung cancer and a transfusion-dependent individual, all affected individuals had elevated red blood cell adenosine deaminase consistent with DBA. We performed whole-exome sequencing on the 5 clinically affected individuals (a male proband, his affected first cousin, 2 affected second cousins, and an affected niece), his obligate carrier sister, and the unaffected father of the proband's niece. Genomic DNA was used to create an enriched multiplexed sequencing library (Nimblegen v2); this was followed by paired-end sequencing using an Illumina HiSeq™. We detected a total of 229,024 exonic nucleotide variants across this family, including 2,484 uncommon (minor allele frequency <5%) non-synonymous amino-acid substitutions. After removing variants that were present in publically available databases (1000Genomes, ESP, Kaviar, and dbSNP) and applying quality control filters, 731 candidate variants remained. We then evaluated these variants for autosomal dominant inheritance in this family. Remarkably, there was only 1 nonsynonymous variant present in all 5 affected individuals and in the obligate carrier, but absent from the unaffected non-obligate carrier parent. This nonsynonymous variant was present in exon 2 of the ribosomal protein S29 (RPS29) gene (chromosome 14q). This region of the RPS29 protein is very highly evolutionarily conserved. Bioinformatic analyses suggested that this variant is highly likely to affect protein function. SIFT, Polyphen 2, and Condel algorithms all predict this variant to be deleterious. RPS29 gene encodes the 40S ribosomal protein S29, which is a component of the small 40S ribosomal subunit and is important for ribosomal RNA processing and ribosome biogenesis. In addition, Zebrafish models of RPS29 mutations have significant defects in hematopoietic stem cell and red blood cell development. We are currently sequencing RPS29 in additional patients with DBA. In summary, whole-exome sequencing has allowed us to uncover another human DBA gene, RPS29, which will likely lead to improved understanding of this complex disorder. Disclosures: No relevant conflicts of interest to declare.

X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation

We identified a family with gray platelet syndrome (GPS) segregating as a sex-linked trait. Affected males had a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of GPS, while obligate carrier females were asymptomatic but had dimorphic platelets on peripheral smear. Associated findings included mild erythrocyte abnormalities in affected males. Linkage analysis revealed a 63 cM region on the X chromosome between markers G10578 and DXS6797, which segregated with the platelet phenotype and included the GATA1 gene. Sequencing of GATA1 revealed a G-to-A mutation at position 759 corresponding to amino acid change Arg216Gln. This mutation was previously described as a cause of X-linked thrombocytopenia with thalassemia (XLTT) but not of gray platelet syndrome. Our findings suggest that XLTT is within a spectrum of disorders constituting the gray platelet syndrome, and we propose that GATA1 is an upstream regulator of the genes required for platelet α-granule biogenesis.

X-Linked Gray Platelet Syndrome Due to a GATA1 Arg216Gln Mutation.

Gray Platelet Syndrome (GPS) is characterized by a variable, mild bleeding diathesis, associated with thrombocytopenia and large, agranular, functionally abnormal platelets. While the disorder has been well-described both biochemically and pathologically, to our knowledge, no genetic mutation has been associated with the disease. Most cases are sporadic, with a few sibships and apparent autosomal kindreds reported. In our investigation, the proband is a healthy 1 year-old female whose father and uncle had recently been diagnosed with GPS. The child had a platelet count of 382 x103 platelets/μl, comprised of a dimorphic population of normal and large, agranular forms. Her CBC and peripheral blood smear were otherwise unremarkable. We subsequently analyzed four generations of this family. In addition to the proband’s father and uncle, several other members had known bleeding tendencies. The symptomatic individuals were invariably males, consistent with a sex-linked pattern of inheritance. Several symptomatic and asymptomatic family members were evaluated by CBC and blood smear. Large, agranular platelets were found in symptomatic males, while obligate carrier females exhibited both normal and abnormal forms. Using a set of fifteen microsatellite markers spanning the X chromosome, a common haplotype was identified in all affected men, their mothers, and their daughters. Aided by the published sequence of the X chromosome, we examined this region for candidate genes. Although the common haplotype between markers GATA144D04 and DXS6797 (Xp11.3-Xq22.3) contains hundreds of genes, only two, GATA1 and WAS, have known associations with thrombocytopenia. PCR amplification and sequencing of a 3′ segment of the GATA-1 promoter and the five coding exons of the GATA-1 gene revealed an G759A missense mutation resulting in an Arg216Gln substitution in exon 4 (NCBI RefSeq: NM_002049) that segregated with the phenotype and was present in all obligate carrier females. This mutation has been previously associated with X-linked thrombocytopenia and beta-thalassemia (XLTT), a syndrome characterized by splenomegaly, thrombocytopenia, and imbalanced globin chain synthesis (Balduini et al, Thromb Haemost. 2004; 91:129). Comparison of the ultrastructural characteristics of the platelets in both disorders and a review of literature on both diseases suggests that XLTT, and the associated mutation in GATA1, could represent one genetic origin for GPS. As carrier females generally display a less severe phenotype than affected males, without thrombocytopenia and with subtle dimorphism on smears, it is possible that this mutation may account for some previously reported “sporadic” cases of GPS.

Cognitive performance in presumed obligate carriers for psychosis

SummaryWe report cognitive performance of a group of individuals who are likely to have transmitted liability to psychosis to their offspring. Out of 230 relatives of patients with psychosis, 27 met our criteria for a presumed obligate carrier, that is a non-psychotic individual who had a parent or a sibling as well as an offspring with psychosis. The presumed obligate carriers showed impairments in verbal memory and in visuospatial manipulations, suggesting that these individuals transmit vulnerability for psychosis to their offspring in terms of a disability to recall verbal information and an impaired capacity to perceive spatial relations.