Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy.

Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by the clinical features of accelerated aging in childhood. Both MAD and HGPS can be caused by mutations in the LMNA gene. In this study, we describe a 2-year-old boy with overlapping features of MAD and HGPS. Mutation analysis of the LMNA gene revealed a homozygous missense change, p.M540T, while only the mother carries the mutation. Uniparental disomy (UPD) analysis for chromosome 1 showed the presence of maternal UPD. Markers in the 1q21.3-q22 region flanking the LMNA locus were isodisomic, while markers in the short arm and distal 1q region were heterodisomic. These results suggest that nondisjunction in maternal meiosis followed by loss of the paternal chromosome 1 during trisomy rescue might result in the UPD1 and homozygosity for the p.M540T mutation observed in this patient.

Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy.

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

PURPOSE: The aim of the study was to determine the actual GJB2 and GJB6 mutation frequencies in North America after several years of generalized testing for autosomal recessive nonsyndromic sensorineural hearing loss to help guide diagnostic testing algorithms, especially in light of molecular diagnostic follow-up to universal newborn hearing screening. METHODS: Mutation types, frequencies, ethnic distributions, and genotype-phenotype correlations for GJB2 and GJB6 were assessed in a very large North American cohort. RESULTS: GJB2 variants were identified in 1796 (24.3%) of the 7401 individuals examined, with 399 (5.4%) homozygous and 429 (5.8%) compound heterozygous. GJB6 deletion testing was performed in 12.0% (888/7401) of all cases. The >300-kb deletion was identified in only nine individuals (1.0%), all of whom were compound heterozygous for mutations in GJB2 and GJB6. Among a total of 139 GJB2 variants identified, 53 (38.1%) were previously unreported, presumably representing novel pathogenic or benign variants. CONCLUSIONS: The frequency and distribution of sequence changes in GJB2 and GJB6 in North America differ from those previously reported, suggesting a considerable role for loci other than GJB2 and GJB6 in the etiology of autosomal recessive nonsyndromic sensorineural hearing loss, with minimal prevalence of the GJB6 deletion.

Mosaicism del(22)(q11.2q11.2)/dup(22)(q11.2q11.2) in a patient with features of 22q11.2 deletion syndrome.

The chromosome 22q11 region is prone to rearrangements, including deletions and duplications, due to the presence of multiple low copy repeats (LCRs). DiGeorge/velo-cardio-facial syndrome is the most common microdeletion syndrome with more than 90% of patients having a common 3-Mb deletion of 22q11.2 secondary to non-homologous recombination of flanking LCRs. Meiotic reciprocal events caused by LCR-mediated rearrangement should theoretically lead to an equal number of deletions and duplications. Duplications of this region, however, have been infrequently reported and vary in size from 3 to 6 Mb. This discrepancy may be explained by the difficulty in detecting the duplication and the variable, sometimes quite mild phenotype. This newly described 22q duplication syndrome is characterized by palatal defects, cognitive deficits, minor ear anomalies, and characteristic facial features. We report on a male with truncus arteriosus and an interrupted aortic arch, immunodeficiency, and hypocalcemia. The patient is mosaic for two abnormal cell lines: a deletion [del(22)(q11.2q11.2)] found in 11 cells and a duplication [dup(22)(q11.2q11.2)] found in 9 cells. Molecular cytogenetic analysis in our patient revealed a 1.5 Mb deletion/duplication, the first duplication reported of this size. Deletion/duplication mosaicism, which is rare, has been reported in a number of cases involving many different chromosome segments. We present the clinical phenotype of our patient in comparison to the phenotypes seen in patients with the 22q11.2 deletion or duplication alone. We propose that this rearrangement arose by a mitotic event involving unequal crossover in an early mitotic division facilitated by LCRs.

Two cases further delineating the Sakoda complex.

Sakoda complex consists of sphenoethmoidal encephalomeningocele, agenesis of the corpus callosum, and cleft lip and/or palate. Associated abnormalities include optic disc dysplasia, microphthalmia, cortical dysgenesis, mental retardation and epilepsy. The etiology remains unknown. We describe two patients with anomalies consistent with the Sakoda complex including the cardinal features of sphenoethmoidal encephalomeningocele and cleft palate. The first patient also has right microphthalmia, optic nerve hypoplasia, diffuse pachygyria, asymmetric ventricles, atrial septal defect, hemivertebrae, and renal abnormalities. The second patient has right microphthalmia, absence of the right hemisphere, and a right bifid thumb. The features of Sakoda complex present in these patients may also overlap with frontonasal dysplasia and morning glory syndrome suggesting shared pathogenic relationships. We propose that the primary malformation of the Sakoda complex is probably genetic. The right hemispheric defect in Patient 2 suggests that at least some cases of Sakoda complex may also be associated with vascular disruption. Thus, more than one pathogenetic process contributes to the phenotypic spectrum of Sakoda complex.

NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory.

PURPOSE: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. METHODS: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. RESULTS: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. CONCLUSIONS: The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated.