A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related 
(ATR) gene was previously reported in two related families displaying Seckel 
Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome 
patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein 
(ATRIP), the partner protein of ATR required for ATR stability and recruitment 
to the site of DNA damage. The patient has compound heterozygous mutations in 
ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational 
change in one ATRIP allele results in a C-terminal truncated protein, which 
impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We 
additionally describe two further unrelated patients native to the UK with the 
same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR 
expression. All patient-derived cells showed defective DNA damage responses that 
can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is 
characterised by microcephaly and growth delay, features also displayed by 
several related disorders including Majewski (microcephalic) osteodysplastic 
primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The 
identification of an ATRIP-deficient patient provides a novel genetic defect for 
Seckel Syndrome. Coupled with the identification of further ATR-deficient 
patients, our findings allow a spectrum of clinical features that can be 
ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP 
patients are characterised by extremely severe microcephaly and growth delay, 
microtia (small ears), micrognathia (small and receding chin), and dental 
crowding. While aberrant bone development was mild in the original ATR-SS 
patient, some of the patients described here display skeletal abnormalities 
including, in one patient, small patellae, a feature characteristically observed 
in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping 
clinical manifestation between the disorders but allows an expanded spectrum of 
clinical features for ATR-ATRIP Seckel Syndrome to be defined.