SNP Shot: Genomic Insights

Kleefstra syndrome is a multi-system disorder impacting various parts of the body. Core features include developmental delays, intellectual disability, significantly impaired or absent speech, and low muscle tone (hypotonia). Individuals with this syndrome often present with a smaller than normal head size (microcephaly) and a broad, short skull (brachycephaly). Characteristic facial features can include fused eyebrows (synophrys), widely set eyes (hypertelorism), a flattened or sunken mid-face (midface hypoplasia), nostrils that point forward (anteverted nares), a prominent jaw (prognathism), turned-out (everted) lips, and an enlarged tongue (macroglossia). Some affected individuals may be born with a high birth weight and experience obesity during childhood.

Individuals with Kleefstra syndrome may also exhibit structural abnormalities in the brain, congenital heart defects, abnormalities of the genitourinary system, seizures, and a heightened susceptibility to severe respiratory infections. During childhood, symptoms related to autism or other developmental disorders affecting communication and social interaction may be observed. Apathy (loss of interest) or catatonia (unresponsiveness) can emerge during adolescence.

Inheritance:

Kleefstra syndrome is generally considered an autosomal dominant condition. This means that a deletion on one copy of chromosome 9 or a mutation in one copy of the EHMT1 gene in each cell is sufficient to cause the syndrome. However, the majority of Kleefstra syndrome cases are not inherited. The genetic change usually occurs spontaneously during the formation of reproductive cells (sperm or eggs) or in early fetal development. Consequently, affected individuals typically have no family history of the condition, although they can potentially pass it on to their offspring. Reproduction is rare in people with Kleefstra syndrome. In rare instances, individuals inherit a chromosome 9 with a missing segment from a parent who is unaffected. In these cases, the unaffected parent carries a balanced translocation, a chromosomal rearrangement where there is no net gain or loss of genetic material. Balanced translocations typically do not cause health problems for the carrier but can become unbalanced when passed to the next generation. Children inheriting an unbalanced translocation may have extra or missing genetic material. Individuals with Kleefstra syndrome who inherit an unbalanced translocation are missing genetic material from the long arm of chromosome 9. A few people with Kleefstra syndrome inherited the chromosome 9q34.3 deletion from an unaffected parent who is mosaic for the deletion. Mosaicism means the parent has the deletion in some cells (including some sperm or egg cells), but not all.