Autosomal recessive microcephaly and micromelia in Cree Indians

Abstract

In a highly consanguineous, predominantly Cree Indian community in northern Saskatchewan, Canada, 14 similarly malformed babies have been born to eight different mothers since 1953. Six of these infants are reported to assist delineation of the syndrome. The major manifestations of the condition are: Intrauterine growth retardation, perinatal death, marked microcephaly, and severe malformations of the limbs, especially the arms. Elbows are fused, forearms are greatly shortened and usually contain only a single bone, and the hands are very abnormal with only two to four malformed digits. Parental consanguinity, a sex ratio close to one, and a 25% segregation ratio all support autosomal recessive inheritance of this syndrome.

Two siblings with microcephaly associated with calcification of cerebral white matter

“…Several cases of inherited microcephaly recorded in the literature showed other associated clinical symptoms: cataracts (Lowry et aL, 1971;Neu et al, 1971;Sagarman, 1973;Scott-Emuakpor et al, 1977), retinopathy (Cantu et aL, 1977;McKusick et al, 1966), abnormal extremities (Lowry et al, 1971;Ives and Houston, 1980) and abnormalities of bone (Zackai et al, 1972). These abnormalities were absent in our cases.…”

Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome

“…1E; see Supplemental Data 1 for a list of all profiled individuals). High-density genome-wide single nucleotide polymorphism (SNP)-microarray genotyping of seven affected individuals and 15 unaffected parents followed by linkage analysis under a recessive inheritance model identified an 852-kb (1.2 cM) locus on Chromosome 21q22.11 definitively associated with the disease with a maximum combined logarithm of odds (LOD) score of 9.2 (Ives and Houston 1980). Gray symbol (top right pedigree) represents a child that died in infancy with limb anomalies, but the specific diagnosis of MMS was not confirmed.…”

“…MMS was first described in 1980 by Ives and Houston (Ives and Houston 1980) in a First Nations population in northern Saskatchewan in Canada. The syndrome's main clinical features are intrauterine growth restriction (IUGR), severe microcephaly, craniofacial dysmorphism, and marked limb malformations.…”

Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in DONSON

“…In 1980, Ives and Houston described 14 malformed newborns born to 8 different mothers of a highly consanguineous Cree Indian family in Canada [Ives and Houston, 1980]. All 14 babies have similar striking manifestations of intrauterine growth restriction, perinatal death as well as cranial and skeletal deformities, summarized in Table 1 .…”