A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters' anomaly

Peters anomaly and Axenfeld-Rieger syndrome (ARS) belong to the overlapping spectrum of disorders summarized as anterior segment dysgenesis (ASD). Five patients from a family with Peters' anomaly and ARS were screened for mutations in the PITX2, CYP1B1 and FOXC1 genes by direct sequencing. All affected family members examined were heterozygous for a single nucleotide substitution, resulting in a nonsense mutation (Q120X) at a highly conserved residue of the FOXC1 gene that is essential for DNA binding. In this pedigree, all affected family members were diagnosed with ARS except for one who shows bilateral Peters' anomaly. Our findings support the role of FOXC1 mutations in the spectrum of ASD.     

Molecular analysis and long-term clinical evaluation of three siblings with Alström syndrome

Alström syndrome is a rare, autosomal recessive disorder characterized by a wide spectrum of clinical features including early‐onset retinal degeneration leading to blindness, sensorineural hearing loss, short stature, obesity, type 2 diabetes, hyperlipidemia and dilated cardiomyopathy. Renal, hepatic and pulmonary dysfunction may occur in the later phases of the disease. The three affected sisters, from a consanguineous Turkish family, with the characteristic features of Alström syndrome, were clinically diagnosed in 1987 and followed for 20 years. DNA sequence analysis of ALMS1, the causative gene in Alström syndrome, identified a novel homozygous disease‐causing mutation, c.8164C>T, resulting in a premature termination codon in exon 10 in each of the three affected sisters. Furthermore, we describe the longitudinal disease progression in this family and report new clinical findings likely associated with Alström syndrome, such as pes planus and hyperthyroidism.     

Spinal extradural arachnoid cysts in lymphedema-distichiasis syndrome

PurposeLymphedema-distichiasis syndrome is characterized by the presence of lower limb lymphedema and supernumerary eyelashes arising from the Meibomian glands. Spinal extradural arachnoid cysts have been observed in some families but their true frequency is unknown. The aim of this study is to determine the frequency of spinal extradural arachnoid cysts in lymphedema distichiasis syndrome.MethodsWe collected clinical information from all 45 living members of a complete family of 48 members and performed molecular analysis of the FOXC2 gene in 30 individuals. We obtained spinal magnetic resonance imaging from all family members with a FOXC2 gene mutation.ResultsTwelve family members carried a mutation in the FOXC2 gene and had clinical features of lymphedema-distichiasis syndrome. Of these, 58% (seven individuals) had extradural arachnoid cysts.DiscussionWe suggest that a follow-up protocol for lymphedema-distichiasis syndrome families should include spinal magnetic resonance imaging for all affected members so that the timing of surgery for removal of these cysts can be optimized.     

A novel nonsense mutation in the EYA1 gene associated with branchio-oto-renal/branchiootic syndrome in an Afrikaner kindred

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the associations of hearing loss, branchial arch defects and renal anomalies. Branchiootic (BO) syndrome is a related disorder that presents without the highly variable characteristic renal anomalies of BOR syndrome. Dominant mutations in the human homologue of the Drosophila eyes absent gene (EYA1) are frequently the cause of both BOR and BO syndromes. We report a South African family of Afrikaner descent with affected individuals presenting with pre-auricular abnormalities and either hearing loss or bilateral absence of the kidneys. Genetic analysis of the pedigree detected a novel EYA1 heterozygous nonsense mutation in affected family members but not in unaffected family members or a random DNA panel. Through mutational analysis, we conclude that this particular mutation is the cause of BOR/BO syndrome in this family as a result of a truncation of the EYA1 protein that ablates the critical EYA homologous region. To the best of our knowledge, this is the first case of BOR/BO syndrome reported in Africa or in those of the Afrikaner descent.     

Novel WEE2 homozygous mutations c.1346C>T and c.949A>T identified in primary infertile women due to unexplained fertilization failure

The occurrence of unexplained fertilization failure can have profound psychological and financial consequences for couples struggling with infertility, and its pathogenesis remains unclear. Increasing evidence highlights genetic basis of unexplained fertilization failure occurrence. Here, we identified one novel homozygous nonsense mutation (c.949A>T), one novel homozygous missense mutation (c.1346C>T), and three reported homozygous mutations (c.585G>C, c.1006_1007insTA, c.1221G>A) in six unrelated probands, showing similar manifestations of unexplained fertilization failure. This finding expands the spectrum of WEE2 mutations, highlighting the critical role of WEE2 in fertilization process, and provides a basis for the prognostic value of testing for WEE2 mutations in primary infertile couples with unexplained fertilization failure.     

Autosomal recessive otofaciocervical syndrome type 2 with novel homozygous small insertion in PAX1 gene

Otofaciocervical syndrome (OTFCS) is described as a single gene disorder of both autosomal dominant and autosomal recessive inheritance. The major clinical features of OTFCS include ear malformations (external/middle/inner ear), facial dysmorphism, shoulder girdle abnormalities, vertebral anomalies, and mild intellectual disability. The autosomal recessive form of OTFCS syndrome (OTFCS2) has been recently reported to be caused due to homozygous mutations in PAX1 gene. Here we report a third family of OTFCS2 phenotype wherein whole exome sequencing identified a novel homozygous small insertion in PAX1 as the underlying genetic cause.     

WDR73-related galloway mowat syndrome with collapsing glomerulopathy

Galloway-Mowat syndrome (GAMOS [MIM 251300]) is a rare autosomal recessive disorder that manifests as a combination of nephrotic syndrome, brain abnormalities and developmental delay. It is a clinically and genetically heterogeneous disease. The WDR73 variations are associated with GAMOS1. Here we report two consanguineous families affected by GAMOS1. In the first family, three sisters are affected and in the second family, only one index case is identified. They all show a nephrotic syndrome, a neurological involvement and a collapsing glomerulopathy. The analysis of mutations of WDR73 revealed a new homozygous missense mutation NM_032856.3 c.293T > C; p.(Leu98Pro) in two patients from the first family, and a new homozygous missense mutation NM_032856.3: c.767G > A; p.(Arg256Gln) in the second one. This study extended the clinical and molecular spectrum of GAMOS1 with other cases associated with collapsing glomerulopathy and two novel WDR73 variations that are most likely pathogenic.     

Familial neurohypophyseal diabetes insipidus associated with a novel mutation in the vasopressin-neurophysin II gene

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder of renal water conservation due to deficiency of arginine vasopressin as the result of mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene that encodes the hormone or its carrier protein. Thirty-one different mutations have been reported. In this study, we evaluated the AVP-NPII gene in a family with FNDI and identified a new mutation (1911Gright curved arrow A) in the coding sequence for NPII in affected family members. This mutation substitutes Tyr for 74 Cys in the NPII moiety. NPII is an intracellular carrier protein for AVP during the axonal transport from the hypothalamus to the posterior pituitary and contains 14 conserved cysteine residues forming 7 disulfide bonds. Because the mutation cosegregates with the phenotype, it is possible that this mutation causes neurohypophyseal diabetes insipidus in this family.     

Novel nonsense mutation of ABHD5 in Dorfman-Chanarin syndrome with unusual findings: a challenge for genotype-phenotype correlation

Dorfman–Chanarin syndrome is a rare neutral lipid disorder characterised by icthyosis, hepatic steatosis and multisystemic involvement of varying magnitude. It is an autosomal recessive disease caused by mutations in the ABHD5 gene. We report a consanguineous family of Afgani origin, with four affected siblings who were found to have a novel homozygous nonsense mutation g. [27606 G > T]; [27606 G > T]. The clinical findings were unusual in the form of early cirrhosis and hepatic decompensation in one sibling, presence of corneal opacities in male siblings and tessellated fundus in all affected children. Steatosis was minimal in liver biopsy specimens and all children had low vitamin D levels. Genotype–phenotype correlations have not been possible in Dorfman–Chanarin syndrome and the present report raises further challenges for the same.     

Spinal extradural arachnoid cysts associated with distichiasis and lymphedema

Spinal extradural arachnoid cysts (SEDAC) are lesions communicating to the subarachnoid space of the spinal canal via a dural defect. SEDAC occupies intraspinal space and sometimes causes neurological disturbances. Although most reported cases are sporadic, several familial cases have been described, suggesting a genetic etiology. Here we report on a family with SEDAC inherited in an autosomal dominant mode. Detailed study showed that the family has the lymphedema-distichiasis syndrome. Among family members examined, a total of ten in two generations manifested all or some of the following features: SEDAC, distichiasis and lymphedema. Seven had spinal cysts, four had both SEDAC and distichiasis, and one had SEDAC distichiasis and lymphedema; three did not have SEDAC. These findings, together with rarity of both distichiasis and lymphedema in the general population, support that all of the ten members were affected with one clinical entity, the lymphedema-distichiasis syndrome. The distribution of features illustrates the variable expressivity of clinical manifestations. Although FOXC2 mutation analysis was not performed in our family, it is likely that SEDAC is a component manifestation of lymphedema-distichiasis syndrome and more consistent in our family than those reported.     

Autosomal recessive familial neurohypophyseal diabetes insipidus with continued secretion of mutant weakly active vasopressin.

Familial neurohypophyseal diabetes insipidus is an autosomal dominant disorder characterized by post-natal development of arginine vasopressin (AVP) deficiency due to mutations in the AVP gene. All published mutations affect the signal peptide or the neurophysin-II carrier protein and are presumed to interfere with processing of the preprohormone, leading to neuronal damage. We studied an unusual Palestinian family consisting of asymptomatic first cousin parents and three children affected with neurohypophyseal diabetes insipidus, suggesting autosomal recessive inheritance. All three affected children were homozygous and the parents heterozygous for a single novel mutation (C301->T) in exon 1, replacing Pro7 of mature AVP with Leu (Leu-AVP). Leu-AVP was a weak agonist with approximately 30-fold reduced binding to the human V2 receptor. Measured by radioimmunoassay with a synthetic Leu-AVP standard, serum Leu-AVP levels were elevated in all three children and further increased during water deprivation to as high as 30 times normal. The youngest child (2 years old) was only mildly affected but had Leu-AVP levels similar to her severely affected 8-year-old brother, suggesting that unknown mechanisms may partially compensate for a deficiency of active AVP in very young children.