Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech.

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS.

Genome scan for cognitive trait loci of dyslexia: Rapid naming and rapid switching of letters, numbers, and colors.

Dyslexia, or specific reading disability, is a common developmental disorder that affects 5-12% of school-aged children. Dyslexia and its component phenotypes, assessed categorically or quantitatively, have complex genetic bases. The ability to rapidly name letters, numbers, and colors from rows presented visually correlates strongly with reading in multiple languages and is a valid predictor of reading and spelling impairment. Performance on measures of rapid naming and switching, RAN and RAS, is stable throughout elementary school years, with slowed performance persisting in adults who still manifest dyslexia. Targeted analyses of dyslexia candidate regions have included RAN measures, but only one other genome-wide linkage study has been reported. As part of a broad effort to identify genetic contributors to dyslexia, we performed combined oligogenic segregation and linkage analyses of measures of RAN and RAS in a family-based cohort ascertained through probands with dyslexia. We obtained strong evidence for linkage of RAN letters to the DYX3 locus on chromosome 2p and RAN colors to chromosome 10q, but were unable to confirm the chromosome 6p21 linkage detected for a composite measure of RAN colors and objects in the previous genome-wide study.

Wenckebach periodicity at rest that normalizes with tachycardia in a family with a NKX2.5 mutation.

A family with asymptomatic Wenckebach atrioventricular block (Wenckebach periodicity [WP]) has been followed at the investigators' institution for >4 decades. In contrast to all reported cases of WP (except in top-ranking athletes) family members have WP at rest that promptly converts to regular sinus tachycardia with exercise. They also have mild apical noncompaction that has been quite stable. Because of apparent autosomal dominant inheritance of the structural and arrhythmia disorders, deoxyribonucleic acid was obtained from 4 affected family members in 2 generations for sequence analysis of the cardiac transcription factor gene NKX2.5. A novel frame-shift mutation (c.959delC) was identified that would result in premature truncation of the protein at residue 293, with loss of the C-terminal 31 amino acids. The responsiveness of WP to exercise, the long-term stability of the WP rhythm, and the mild asymptomatic structural features expand the phenotypic presentation of diseases related to mutations in NKX2.5. In addition, the physiology of WP is reviewed in these subjects and in highly conditioned athletes. In conclusion, the investigators report familial stable WP and ventricular noncompaction caused by a mutation in NKX2.5.

Autosomal dominant familial dyskinesia and facial myokymia: single exome sequencing identifies a mutation in adenylyl cyclase 5.

BACKGROUND: Familial dyskinesia with facial myokymia (FDFM) is an autosomal dominant disorder that is exacerbated by anxiety. In a 5-generation family of German ancestry, we previously mapped FDFM to chromosome band 3p21-3q21. The 72.5-Mb linkage region was too large for traditional positional mutation identification. OBJECTIVE: To identify the gene responsible for FDFM by exome resequencing of a single affected individual. PARTICIPANTS: We performed whole exome sequencing in 1 affected individual and used a series of bioinformatic filters, including functional significance and presence in dbSNP or the 1000 Genomes Project, to reduce the number of candidate variants. Co-segregation analysis was performed in 15 additional individuals in 3 generations. MAIN OUTCOME MEASURES: Unique DNA variants in the linkage region that co-segregate with FDFM. RESULTS: The exome contained 23 428 single-nucleotide variants, of which 9391 were missense, nonsense, or splice site alterations. The critical region contained 323 variants, 5 of which were not present in 1 of the sequence databases. Adenylyl cyclase 5 (ADCY5) was the only gene in which the variant (c.2176G>A) was co-transmitted perfectly with disease status and was not present in 3510 control white exomes. This residue is highly conserved, and the change is nonconservative and predicted to be damaging. CONCLUSIONS: ADCY5 is highly expressed in striatum. Mice deficient in Adcy5 develop a movement disorder that is worsened by stress. We conclude that FDFM likely results from a missense mutation in ADCY5. This study demonstrates the power of a single exome sequence combined with linkage information to identify causative genes for rare autosomal dominant mendelian diseases.

Genome scan of a nonword repetition phenotype in families with dyslexia: evidence for multiple loci.

To understand the genetic architecture of dyslexia and identify the locations of genes involved, we performed linkage analyses in multigenerational families using a phonological memory phenotype--Nonword Repetition (NWR). A genome scan was first performed on 438 people from 51 families (DS-1) and linkage was assessed using variance components (VC), Bayesian oligogenic (BO), and parametric analyses. For replication, the genome scan and analyses were repeated on 693 people from 93 families (DS-2). For the combined set (DS-C), analyses were performed with all three methods in the regions that were identified in both samples. In DS-1, regions on chromosomes 4p, 6q, 12p, 17q, and 22q exceeded our initial threshold for linkage, with 17q providing a parametric LOD score of 3.2. Analysis with DS-2 confirmed the locations on chromosomes 4p and 12p. The strongest VC and BO signals in both samples were on chromosome 4p in DS-C, with a parametric multipoint LOD(max) of 2.36 for the 4p locus. Our linkage analyses of NWR in dyslexia provide suggestive and reproducible evidence for linkage to 4p12 and 12p in both samples, and significant evidence for linkage to 17q in one of the samples. These results warrant further studies of phonological memory and chromosomal regions identified here in other datasets.

Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia.

Dyslexia is a common heterogeneous disorder with a significant genetic component. Multiple studies have replicated the evidence for linkage between variously defined phenotypes of dyslexia and chromosomal regions on 15q21 (DYX1) and 6p22.2 (DYX2). Based on association studies and the possibility for functional significance of several polymorphisms, candidate genes responsible for the observed linkage signal have been proposed-DYX1C1 for 15q21, and KIAA0319 and DCDC2 for 6p22.2. We investigated the evidence for contribution of these candidate genes to dyslexia in our sample of multigenerational families. Our previous quantitative linkage analyses in this dataset provided supportive evidence for linkage of dyslexia to the locus on chromosome 15, but not to the locus on chromosome 6. In the current study, we used probands from 191 families for a case control analysis, and proband-parent trios for family-based TDT analyses. The observation of weak evidence for transmission disequilibrium for one of the two studied polymorphisms in DYX1C1 suggests involvement of this gene in dyslexia in our dataset. We did not find evidence for the association of KIAA0319 or DCDC2 alleles to dyslexia in our sample. We observed a slight tendency for an intronic deletion in DCDC2 to be associated with worse performance on some quantitative measures of dyslexia in the probands in our sample, but not in their parents.