1. Does the patient meet clinical criteria for diagnosis (N-H CSS)?
Molecular testing for 11p15 and upd(7)mat1
Yes (score ≥4/6) OR
No but continued clinical suspicion
(score 3/6) 2
No (score ≤3/6)
Diagnosis not confirmed
Does the patient have relative microcephaly?
Diagnosis not confirmed.
Consider differential diagnosis (Table 2)
Consider differential diagnosis (Table 3)
Molecular testing as per differential diagnosis
Clinical Features consistent with differential diagnosis?
Yes No
Consider additional molecular testing:
CNV/ 14q32 analysis; then:
upd(16)mat, upd(20)mat, CDKN1C / IGF2 mutation,
(c) alternative tissue
Positive
Negative
Negative
Diagnosis not confirmed
What is the N-H CSS Score?
Clinical SRS5
≥ 5/6
Does the patient have relative macrocephaly and protruding forehead ?
4/6
3/6
Yes4 No No
Positive
Molecular diagnosis confirmed: SRS
Alternative molecular diagnosis3
1Arrange CNV analysis BEFORE other investigations if patient has significant unexplained global developmental delay/ intellectual disability, and /or relative microcephaly. 2Studies have excluded 11p15 LOM and upd(7)mat in patients with IUGR and postnatal growth retardation alone; some patients, particularly those with upd(7)mat or children under 2 years, score 3/6 (see text for details). 3Insufficient evidence at present to determine relationship to SRS, with the exception of tissue mosaicism 4Unless evidence of catch-up growth by 2 years . 5Previously known as idiopathic SRS.

2. A B Telomeric domain Centromeric domain mat pat mat pat H19 CDKN1C
IGF2
mat
pat
IGF2/H19
IG DMR
CDKN1C
KCNQ1
KCNQ1OT1
TSS-DMR B
CTCF
CTCF
CTCF
CTCF
CTCF
CTCF
CTCF
mat
H19 A1 B1 B2 B3 B4 A2 B5 B6 B7
enhancers
CBS6
CBS5
CBS4
CBS3
CBS2
CBS1
CBS7
pat A1 B1 B2 B3 B4 A2 B5 B6 B7
IGF2

3. X X Paternal IGF2/H19 IG DMR LOM Maternal duplication of both domains
Maternal duplication of the centromeric domain X
MaternaI CDKN1C gain of function mutation X
PaternaI IGF2 loss of function mutation