Heterozygous mutations in cause juvenile peroxisomal D-bifunctional protein deficiency.

Objective: To determine the genetic cause of slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism in 5 patients from 3 different families.

Methods: The patients comprised 2 sib pairs and 1 sporadic patient. Clinical assessment included history, physical examination, and brain MRI.

Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.

Objective: To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy.

Methods: Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced.

Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology.

Advances in understanding the etiology of Parkinson disease have been driven by the identification of causative mutations in families. Genetic analysis of an Australian family with three males displaying clinical features of early-onset parkinsonism and intellectual disability identified a ∼45 kb deletion resulting in the complete loss of RAB39B. We subsequently identified a missense mutation (c.

Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.

Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.

Autosomal dominant vasovagal syncope: clinical features and linkage to chromosome 15q26.

Objective: To establish the occurrence of an autosomal dominant form of vasovagal syncope (VVS) by detailed phenotyping of multiplex families and identification of the causative locus.

Methods: Patients with VVS and a family history of syncope were recruited. A standardized questionnaire was administered to all available family members and medical records were reviewed.

Familial adult myoclonic epilepsy: recognition of mild phenotypes and refinement of the 2q locus.

Background: Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures.

Objectives: To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus.

Design: Observational family study.

Reducing the exome search space for mendelian diseases using genetic linkage analysis of exome genotypes.

Many exome sequencing studies of Mendelian disorders fail to optimally exploit family information. Classical genetic linkage analysis is an effective method for eliminating a large fraction of the candidate causal variants discovered, even in small families that lack a unique linkage peak. We demonstrate that accurate genetic linkage mapping can be performed using SNP genotypes extracted from exome data, removing the need for separate array-based genotyping.

Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15.

Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis.

Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects.

Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population.

Objectives: We investigated the cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) that segregated in 2 consanguineous Iranian families.

Methods: Otologic and audiometric examinations were performed on affected members of each family. Genome-wide parametric multipoint linkage mapping using a recessive model was performed with Affymetrix 50K GeneChips or short tandem repeat polymorphisms.