Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ∼ 45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy-associated genes in subjects versus controls, confirmed in a second ethnically discrete neuropathy cohort, suggesting that mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HPMVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

Autoimmune polyendocrinopathy associated with ring chromosome 18.

Phenotypic and clinical features of individuals with ring chromosome 18 [r(18)] vary with the extent of deletion of the short (18p-) or long arm (18q-). Most patients with r(18), therefore, demonstrate a clinical spectrum of both 18p- and 18q- deletions. Short stature, microcephaly, mental and motor retardation, craniofacial dysmorphism and extremity abnormalities are the most commonly reported features in patients with r(18). Abnormalities of chromosome 18, especially 18p- syndrome, are often reported with autoimmune thyroid disease and growth hormone deficiency, but reports of endocrine abnormalities associated with r(18) are rare. Here, we report a case of an African-American female with hyperthyroidism, type 1 diabetes mellitus, vitiligo and IgA deficiency associated with a r(18) chromosome complement. This patient additionally had mild intellectual disability and dysmorphic features. Karyotype analysis showed a de novo ring chromosome 18 (deletion 18q23-18qter and deletion 18p11.3-18pter). Although this unique association of autoimmune polyglandular endocrinopathy with ring chromosome 18 could be coincidental, we speculate that a gene or genes on chromosome 18 might play a role in the autoimmune process.

Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.

PURPOSE: The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity. METHODS: Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay. RESULTS: Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ≥95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls. CONCLUSIONS: Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.

Positive association between congenital anomalies and risk of neuroblastoma.

BACKGROUND: Case reports and epidemiological studies have suggested a relationship between congenital anomalies and childhood cancer, but some potential associations remain inconsistent. In this study, we investigated the association between congenital anomalies and neuroblastoma. PROCEDURE: We used data of a case-control study on neuroblastoma conducted from 1992 to 1994, including 538 children aged 0-19 years with newly diagnosed, histologically confirmed neuroblastoma and 504 controls identified by telephone random-digit dialing and matched to cases on date of birth. Information on congenital anomalies and potential confounding factors was collected through maternal telephone interviews using a structured questionnaire. We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusted for reference age at diagnosis, mother's educational level, mother's race, and household income at birth. RESULTS: An association between the maternal report of any congenital anomalies and neuroblastoma (OR = 2.58; CI = 1.57-4.25) was observed. Neuroblastoma risk increased with increasing number of anomalies per child (OR = 3.90, CI = 1.27-11.9 for two anomalies or more), and when we restricted analyses to major anomalies (OR = 7.53, CI = 2.23-25.5). Genitourinary anomalies (OR = 5.84, CI = 1.67-20.4) and cardiac anomalies (OR = 4.27, CI = 1.22-15.0) had an elevated, but imprecise neuroblastoma risk. CONCLUSIONS: Our findings support the hypothesis of an association between neuroblastoma and congenital, especially urogenital and cardiac, anomalies.