A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3

six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, craniofacial dysmorphism - consisted of a triangular face with a prominent forehead and midface hypoplasia, severe failure to thrive with normal birth weights, and over-riding toes, with clinodactyly or syndactyly. Magnetic resonance imaging demonstrated thinning of the corpus callosum and paucity of white matter. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia.

Genome-wide linkage analysis was carried using single nucleotide polymorphism arrays for nineteen family members and the HomozigosityMapper and SuperLink softwares (1, 2). Whole-exome-and-genome sequencing was performed for three individuals and analysed using the Qiagen Clinical Insight software and our in-house database of ~700 samples.

A single ~4 Mbp disease-associated locus was identified on chromosome 7, between rs6952664 and rs13234589 (maximal LOD score of 5.01). Next generation sequencing analysis identified no non-synonymous pathogenic biallelic variants within this locus. Notably, no variants were found in any of the genes previously associated with cases of partially resembling syndromes, such as Russell-silver, Seckel, or Zellweger.

Considering the consanguinity of the kindred and the homozygosity locus shared by the affected individuals, recessive heredity is the most likely, although other forms of monogenic heredity, such as genomic imprinting, cannot be entirely ruled out. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.