Sibling recurrence in intellectual disability of unknown cause

To the Editor : Even after thorough clinical and laboratory evaluation, causation remains unknown in approximately 50% of all cases of intellectual disability (ID) (1–5). This circumstance calls for the frequent use of empiric recurrence rates in reproductive counseling. A 1998 review noted that studies since 1971 found recurrence rates from 2% to 26% for mild ID of unknown cause (6–10). Herein, we report recurrence rates in a cohort of 422 American families with ID of unknown cause stratified by parental status and the sex, intelligence quotient (IQ), racial/ethnic background, and head circumference of the proband. Probands with an IQ ≤70 and impairments in adaptive behavior (11) who had at least one younger sibling over 5 years of age were eligible for this study. Information on siblings or other family members came from interviews/records review. Exclusion criteria were first cousin or closer consanguinity, dysmorphism suggesting a syndrome, major congenital abnormalities, cerebral palsy, a clinical or laboratory diagnosis, balanced cytogenetic rearrangements, or other known cause of ID. Data from siblings in 550 families were reviewed; however, 128 families were excluded. Among the remaining 422 families, 64% of probands were male. Fifty-one percent of probands were non-Hispanic black, 48% were non-Hispanic white, and 1% were from other racial/ethnic backgrounds. Ninety-six percent of probands resided in South Carolina. The probands had an average IQ of 41, average head circumference at the 46th percentile, and an average birth weight of 3142 g. Twenty-eight percent had seizures, 26% a form of psychosis, and 8% had autism. All probands were evaluated by clinical geneticists at the Greenwood Genetic Center in South Carolina from 1988 to 2009. Eighty-five percent had been karyotyped, 73% had fragile X studies, 41% had plasma amino acid analysis, 19% had urine metabolic screening, 14% had FISH microdeletion analyses, 12% had subtelomere studies, 6% had cranial imaging, and 4% had microarray comparative genomic hybridization analyses. All of these tests on the probands were normal. There were 950 full siblings born after the 422 probands, and 16% had ID (Table 1). Sixteen percent of 152 half siblings and 11% of 505 prior siblings had ID. The recurrence rate in full siblings was found to be approximately 12% (95% confidence interval ranges from 10% to 14%) if the parents had normal intellectual function, but increased dramatically if one or both parents had ID (Table 1). This increased rate has been observed in other studies (12–14). The recurrence rate was significantly higher if the proband was male (Table 2). An Australian study found lower recurrence rates of 10% in siblings of male and 8% in siblings of female probands (15). A study of probands with nonsyndromal ID in British Columbia also found lower recurrence rates of 4% in subsequent siblings (9). Similar rates of ID among all siblings of male (14%) and female (15%) probands were found among Israeli families (10). The severity of ID significantly influenced the recurrence rate. Intelligence quotient scores <35 in the proband were associated with recurrence rates in the 3–6% range, whereas recurrence rates were 10–22% if the proband’s IQ was ≥35 (Table 2). These findings are in agreement with those of Bundey and Carter (14), who cited recurrence rates in siblings of probands with IQs ≤50 of 3–8% in a review of five previous studies. In summary, the recurrence rate in full siblings was found to be approximately 12% with parents of normal intellectual function, but increased dramatically if one or both parents had ID. The recurrence rate was significantly higher if the proband or subsequent sibling was male. Recurrence rates significantly increased along with the IQ in the proband. Recurrence rates were not significantly different between non-Hispanic whites and non-Hispanic blacks. Siblings of probands with macrocephaly or microcephaly did not have a significantly increased recurrence rate.