9q22 Deletion--first familial case.

Area of Science:

• Human Genetics
• Genomic Medicine
• Developmental Biology

Background:

• Constitutional 9q22 deletions are rare, with only 29 cases reported, typically sporadic and associated with Gorlin syndrome due to PTCH1 gene haploinsufficiency.
• Previous constitutional 9q22 deletions have been sporadic, often linked to PTCH1 gene mutations causing Gorlin syndrome or nevoid basal cell carcinoma syndrome.

Observation:

• A 5.3 Mb microdeletion at 9q22.2q22.32 was identified in two siblings with intellectual disability and their unaffected father using array comparative genomic hybridization (CGH).
• The microdeletion encompasses 30 genes, including ROR2 and SYK, but notably excludes the PTCH1 gene.
• Shared mild dysmorphic features include downslanting palpebral fissures, narrow nose, long philtrum, specific ear morphology, and small toenails. Affected individuals also exhibit dysarthria and recurrent infections.

Findings:

• This is the first reported familial constitutional 9q22 deletion, distinct from previously described sporadic cases.
• The identified deletion does not involve the PTCH1 gene, differentiating it from typical Gorlin syndrome-associated deletions.
• The deletion leads to variable phenotypes, including intellectual disability in siblings but not in the father, indicating variable penetrance.

Implications:

• This familial 9q22 deletion provides new insights into genotype-phenotype correlations beyond PTCH1.
• The variable expressivity and penetrance of this deletion present challenges for accurate genetic counseling.
• Further research is needed to understand the specific roles of ROR2, SYK, and other deleted genes in the observed phenotype.