22q11.2 deletion syndrome – new research into the wide variety and great variability of symptoms

Frontiers in Genetics May 2017 – 22q11.2​ ​deletion​ ​syndrome​ ​has​ ​a​ ​wide​ ​variety​ ​of​ ​symptoms,​ ​including​ ​(but​ ​not​ ​limited​ ​to)​ ​congenital heart​ ​disease,​ ​hypocalcemia​ ​(where​ ​the​ ​blood​ ​has​ ​too​ ​little​ ​calcium),​ ​immunological​ ​disorders,​ ​and psychiatric​ ​disorders.​ ​Palatal,​ ​craniofacial,​ ​skeletal,​ ​and​ ​gastroenterological​ ​anomalies​ ​are​ ​also​ ​common symptoms.​ ​Along​ ​with​ ​the​ ​range​ ​of​ ​symptoms,​ ​the​ ​severity​ ​differs​ ​from​ ​patient​ ​to​ ​patient.

To​ ​discover​ ​some​ ​of​ ​the​ ​reasons​ ​for​ ​this​ ​great​ ​variability​ ​in​ ​symptoms​ ​the​ ​authors​ ​analyzed​ ​two​ ​genetic features:​ ​a)​ ​exact​ ​position​ ​of​ ​the​ ​breakpoints,​ ​and​ ​b)​ ​structure​ ​of​ ​copy​ ​number​ ​variants​ ​(CNV)​ ​associated with​ ​deletions​ ​22q11.2.
The​ ​study​ ​group​ ​consisted​ ​of​ ​21​ ​individuals​ ​-​ ​9​ ​males​ ​and​ ​12​ ​females​ ​-​ ​with​ ​a​ ​known​ ​22q11.2​ ​deletion, ranging​ ​in​ ​age​ ​from​ ​3​ ​months​ ​to​ ​37​ ​years.​ ​Of​ ​the​ ​21​ ​individuals​ ​tested,​ ​18​ ​had​ ​large,​ ​similar​ ​deletions​ ​in the​ ​22q11.2​ ​region​ ​(around​ ​3​ ​Mb​ ​in​ ​size).​ ​In​ ​these​ ​18​ ​individuals,​ ​this​ ​“common”​ ​deletion​ ​occurs​ ​withincertain​ ​breakpoints​ ​in​ ​the​ ​chromosome​ ​(specifically,​ ​between​ ​regions​ ​labeled​ ​LCR22-A​ ​and​ ​LCR22-D). The​ ​genes​ ​within​ ​these​ ​breakpoints​ ​do​ ​not​ ​contribute​ ​to​ ​the​ ​clinical​ ​signs​ ​of​ ​22q11.2​ ​deletion​ ​and, therefore,​ ​position​ ​of​ ​the​ ​breakpoints​ ​is​ ​not​ ​a​ ​potential​ ​reason​ ​for​ ​the​ ​variability​ ​in​ ​symptoms​ ​between individuals.

CNVs​ ​can​ ​influence​ ​the​ ​expression​ ​of​ ​the​ ​genes​ ​they​ ​inhabit,​ ​which​ ​can​ ​interact​ ​with​ ​other​ ​genes​ ​in​ ​the genome.​ ​The​ ​3​ ​Mb​ ​region​ ​contains​ ​about​ ​50​ ​genes,​ ​but​ ​the​ ​functions​ ​of​ ​all​ ​of​ ​these​ ​genes​ ​has​ ​not​ ​been fully​ ​explored.​ ​A​ ​large​ ​number​ ​of​ ​the​ ​genes​ ​in​ ​this​ ​region,​ ​are​ ​related​ ​to​ ​mitochondrial​ ​functions​ ​and non-coding​ ​RNAs​ ​(which​ ​include​ ​microRNAs).​ ​Mitochondria​ ​are​ ​necessary​ ​for​ ​providing​ ​energy​ ​to​ ​cells during​ ​development;​ ​therefore,​ ​some​ ​of​ ​the​ ​symptoms​ ​above​ ​may​ ​occur​ ​if​ ​the​ ​individual​ ​does​ ​not develop​ ​properly​ ​before​ ​birth.​ ​In​ ​persons​ ​with​ ​del​ ​22q11.2​ ​the​ ​authors​ ​found​ ​unusually​ ​high​ ​number​ ​of CNV​ ​affecting​ ​virtually​ ​all​ ​chromosomes,​ ​and​ ​almost​ ​all​ ​affected​ ​individuals​ ​had​ ​CNV​ ​which​ ​include microRNA​ ​genes.​ ​However,​ ​the​ ​authors​ ​did​ ​not​ ​provide​ ​information​ ​about​ ​spectrum​ ​and​ ​distribution​ ​of CNV​ ​in​ ​the​ ​control​ ​group​ ​of​ ​persons.

In​ ​summary,​ ​this​ ​study​ ​aimed​ ​to​ ​find​ ​the​ ​reason​ ​behind​ ​the​ ​variability​ ​in​ ​the​ ​severity​ ​of​ ​the​ ​symptoms​ ​of the​ ​22q11.2​ ​deletion​ ​by​ ​exploring​ ​the​ ​genes​ ​in​ ​the​ ​breakpoints​ ​of​ ​the​ ​deletion,​ ​and​ ​the​ ​common​ ​CNVs shared​ ​by​ ​individuals​ ​with​ ​the​ ​deletion.​ ​The​ ​evidence​ ​from​ ​the​ ​study​ ​shows​ ​that​ ​the​ ​genes​ ​within​ ​the breakpoints​ ​do​ ​not​ ​contribute​ ​to​ ​the​ ​variability.​ ​The​ ​CNVs,​ ​however,​ ​with​ ​their​ ​connection​ ​to​ ​microRNA production,​ ​may​ ​contribute.​ ​More​ ​research​ ​is​ ​necessary​ ​to​ ​determine​ ​if​ ​these​ ​genes​ ​within​ ​the​ ​CNVs directly​ ​relate​ ​to​ ​the​ ​symptoms​ ​of​ ​the​ ​deletions.