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1.
Eur J Med Genet ; 59(11): 577-583, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27667191

ABSTRACT

Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form.


Subject(s)
Abnormalities, Multiple/genetics , Amelogenesis Imperfecta/genetics , Casein Kinase I/genetics , Cleft Palate/genetics , Dementia/genetics , Diagnosis, Differential , Epilepsy/genetics , Exophthalmos/genetics , Extracellular Matrix Proteins/genetics , Microcephaly/genetics , Osteosclerosis/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/mortality , Abnormalities, Multiple/physiopathology , Adolescent , Amelogenesis Imperfecta/diagnosis , Amelogenesis Imperfecta/mortality , Amelogenesis Imperfecta/physiopathology , Bone Diseases, Developmental/genetics , Bone Diseases, Developmental/mortality , Bone Diseases, Developmental/physiopathology , Cleft Palate/diagnosis , Cleft Palate/mortality , Cleft Palate/physiopathology , Dementia/diagnosis , Dementia/mortality , Dementia/physiopathology , Epilepsy/diagnosis , Epilepsy/mortality , Epilepsy/physiopathology , Exophthalmos/diagnosis , Exophthalmos/mortality , Exophthalmos/physiopathology , Female , Humans , Learning Disabilities/genetics , Learning Disabilities/physiopathology , Male , Microcephaly/diagnosis , Microcephaly/mortality , Microcephaly/physiopathology , Osteosclerosis/diagnosis , Osteosclerosis/mortality , Osteosclerosis/physiopathology , Phenotype , Seizures/genetics , Seizures/physiopathology
2.
Eur J Med Genet ; 59(10): 507-11, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27633571

ABSTRACT

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. It is the mildest form known to date of peroxisome biogenesis disorder caused by hypomorphic mutations of PEX1 and PEX6 genes. We report on a second Moroccan family with Heimler syndrome with early onset, severe visual impairment and important phenotypic overlap with Usher syndrome. The patient carried a novel homozygous missense variant c.3140T > C (p.Leu1047Pro) of PEX1 gene. As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with HS, patients with SNHL and retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes.


Subject(s)
Adenosine Triphosphatases/genetics , Amelogenesis Imperfecta/genetics , Hearing Loss, Sensorineural/genetics , Membrane Proteins/genetics , Nails, Malformed/genetics , Retinitis Pigmentosa/genetics , ATPases Associated with Diverse Cellular Activities , Amelogenesis Imperfecta/complications , Child , Child, Preschool , DNA Mutational Analysis , Female , Hearing Loss, Sensorineural/complications , Hearing Loss, Sensorineural/physiopathology , Homozygote , Humans , Male , Mutation , Nails, Malformed/complications , Pedigree , Peroxisomal Disorders/genetics , Peroxisomal Disorders/physiopathology , Phenotype , Retinitis Pigmentosa/complications , Retinitis Pigmentosa/physiopathology
3.
Am J Hum Genet ; 97(4): 535-45, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26387595

ABSTRACT

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.


Subject(s)
Adenosine Triphosphatases/genetics , Amelogenesis Imperfecta/genetics , Fibroblasts/pathology , Hearing Loss, Sensorineural/genetics , Membrane Proteins/genetics , Mutation/genetics , Nails, Malformed/genetics , Peroxisomes/pathology , ATPases Associated with Diverse Cellular Activities , Adolescent , Adult , Case-Control Studies , Cells, Cultured , Child , Child, Preschool , Female , Fibroblasts/metabolism , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Pedigree , Peroxisomes/metabolism , Phenotype , Prognosis , Survival Rate , Young Adult
4.
PLoS Genet ; 11(3): e1005097, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25807530

ABSTRACT

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.


Subject(s)
Aspartate-tRNA Ligase/genetics , Leigh Disease/genetics , RNA, Transfer, Amino Acyl/genetics , Adult , Amino Acid Sequence/genetics , Animals , Aspartate-tRNA Ligase/biosynthesis , Deafness/genetics , Deafness/pathology , Ear, Inner/metabolism , Ear, Inner/pathology , Female , Fibroblasts , Gene Expression/genetics , Genetic Predisposition to Disease , Humans , Leigh Disease/pathology , Male , Mice , Middle Aged , Mitochondria/genetics , Mitochondria/pathology , Mutation, Missense/genetics , Oxygen Consumption/genetics , Pedigree
5.
Mol Syndromol ; 5(5): 218-28, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25337069

ABSTRACT

Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the distal limb joints without a neuromuscular disease. Mutations in at least 8 different genes have been shown to cause DA. Here, we report a 4-generation Indian family with 18 affected members presenting variable features of camptodactyly, brachydactyly, syndactyly, decreased flexion palmar creases, ulnar deviation of the hands, sandal gaps and club feet. We undertook exome sequencing of 3 distantly related affected individuals. Bioinformatics filtering revealed a known pathogenic missense mutation c.188G>A (p.Arg63His) in TNNT3 in all 3 affected individuals that segregated with the phenotype. The affected individuals exhibit significant phenotypic variability. This study demonstrates the value of exome sequencing helping to define the causative variant in genetically heterogeneous disorders.

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