Table 4 Summary characteristics of group B articles

Butler et al. (2005), USA

[14]

Referrals to general genetics or autism clinics for diagnosis, medical management and/or genetic testing. For 6 participants, DNA was obtained from the Autism Genetic Resource Exchange and selected based on the diagnosis of classical autism and having macrocephaly

3 (18)

3 (M)

2 years 6 months–4 years

Autism Diagnostic Interview-Revised 5, clinical genetics evaluation. Psycho-behavioural examinations. Review of family and medical histories

N/A

Severe speech delay (n = 2), developmental delay (n = 2), speech apraxia (n = 1), short attention span (n = 2), language delay (n = 1) and ASD (n = 3)

0.89

Buxbaum et al. (2007), International

[12]

Recruited through the Paris Autism Research International Sibpair study at clinical centres internationally. Further recruitment by the Mount Sinai School of Medicine and/or the Autism Genetic Resource Exchange (AGRE). Participants with head circumference ≥ 2 SD were studied

5 (88)

3 (M)

3 years 6 months–26 years

Clinical evaluation following DSM-IV criteria for ASD, Autism Diagnostic Interview-Revised or the Asperger Syndrome Diagnostic Interview

N/A

Asperger Syndrome (n = 1), ASD (n = 4), developmental delay (n = 1), speech and language delay (n = 1) and delayed motor skills (n = 1)

0.89

*Kato et al. (2018), Japan

[51]

Genetic investigation of 33 Japanese patients with macrocephaly and development delay. No referral information given

6 (33)

2 (M)

4–6 years

Kinder Infant Development Scale (KIDS), Tanaka-Binet Intelligence Scale V, Kyoto Scale of Psychological Development

1 child described as having “autistic tendencies” with no further details provided

Developmental delay (n = 1), motor delay (n = 4), speech delay (n = 3), autistic tendencies (n = 1)

Developmental Quotients; 76, 65, 85, 59, 54, 30

0.67

Klein et al. (2013), USA

[52]

Chart review of patients seen at UCLA genetics clinic from 2008 to 2011 with ASD and macrocephaly. Patients are referred to this clinic by a neurologist or a psychiatrist who had evaluated the patient using various autism screening and assessment measures

5 (33)

5 (M)

2 years 6 months–15 years

Autism Diagnostic Observation Schedule, Pre-Linguistic Autism Diagnostic Observation Schedule, Checklist for Autism in Toddlers, and Screening Tool for Autism in Toddlers & Young Children

N/A

ASD

0.78

*McBride et al. (2010), USA

[53]

Medical records searched of patients who have had PTEN clinical sequencing tests performed from January 1, 2008, to June 30, 2009, at a Children’s hospital.

4 (93)

1 (M)

8 months–9 years 4 months

Medical records review, with some reporting use of Autism Diagnostic Observation Schedule

Diagnoses made using DSM-IV criteria (ADOS used for confirmation in 20%)

Developmental delay (n = 2), ASD (n = 2), mental retardation (n = 1), affective disorder (n = 1), behavioural problems (oppositional and anger, n = 1)

0.67

Negishi et al. (2017), Japan

[54]

Unknown. All patients had increased head circumference and neurological symptoms (such as developmental delay and epilepsy)

3 (13)

0 (M)

4 years 2 months–4 years 9 months

Kinder Infant Development Scale (KIDS)

N/A

Developmental delay

Developmental quotient = 59, 76 and 85

0.56

O’Roak et al. (2012), USA

[55]

Autistic probands recruited from Simons Simplex Collection. Probes used to target 44 ASD candidate genes

3 (2495)

2 (M)

Unknown

Unknown

N/A

ASD

Non-verbal IQ = 50, 33, 77

0.56

*Orrico et al. (2009), Italy

[56]

Patients referred for genetic counselling due to macrocephaly associated with cognitive and behavioural impairment with or without features of ASD.

3 (40)

2 (M)

5–9 years

Vineland Adaptive Behaviour Scales and Childhood Autism Rating Scale (CARS)

Classification of ASD based on CARS

Moderately impaired communication, daily living skills, social interaction and motor skills (n = 1), severe ASD (n = 1), overall low adaptive behaviour and communication, daily living skills, socialisation and motor skills (n = 1)

0.78

*Saskin et al. (2017), USA

[57]

Analysis of whole-exome data from National Database for Autism Research.

6 (2392 families)

Unknown

Unknown

Unknown

ASD classification (further details unknown)

ASD (n = 2) and developmental delay (n = 1)

0.56

*Varga et al. (2009), USA

[58]

Search of medical records of a list of patients who had clinical PTEN gene sequencing ordered between January 1, 2005, and December 31, 2007, at a children’s hospital. Records were most commonly requested from molecular and human genetics and neurology and developmental disabilities/autism clinics.

11 (114)

8 (M)

3 months–35 years

Variety of autism assessments including Autism Diagnostic Observation Scale and search of medical records

Indicated in medical records based on DSM-IV criteria. Further information shows a range of professionals diagnosed ASD including developmental paediatricians, multidisciplinary evaluation, neurologists, psychiatrics or other physicians. ADOS used for confirmation for 13 participants

ASD (n = 5), developmental delay without ASD (n = 6) and expressive speech delay (n = 1)

0.67

*Wong et al. (2018), Hong Kong

[59]

Patients with suspected PHTS (indicated by autistic features and/or neurodevelopmental delays and macrocephaly) were referred for assessment and genetic testing to the Clinical Genetic Service (CGS) of Department of Health between January 1995 and September 2016. Records were also retrieved

3 (13)

2 (M)

9–10 years

Unknown

“Autism” or “Autistic features” stated in clinical features (further details on how this was diagnosed is not available)

Intellectual disability (n = 1), Autistic features (n = 3) and developmental delay (n = 2)

0.67

Yeung et al. (2017), Hong Kong

[60]

Patients recruited from January 2013 to December 2016 at the Duchess of Kent Children’s Hospital Child Assessment Center. Patients with ASD/DD and macrocephaly were assessed by a developmental paediatrician and allied health professionals. No further referral information

4 (21)

4 (M)

1 year 8 months–8 years 2 months

Griffiths Mental Developmental Scales-Extended Revised if less than 72 months, Hong Kong Wechsler Intelligence Scale if over 72 months, Autism Diagnostic Observation Schedule

N/A

Mild Global developmental delay (n = 3), moderate developmental delay (n = 1)

0.78