Supplementary Material

Supplementary table 1. Summary of family studies. Statistical measures are stated where possible.
Study Disease/trait Sample Techniques Results

Bowden et The G45R variant in the ADIPOQ

al. [56] gene was identified in 2 families
Linkage-analysis, with lower mean plasma levels o
80 families WES, Sanger adiponectin. The allele frequency
Adiponectin level sequencing. was 18% in the 2 families versus
1.1% in the cohort. A total of 27
individuals from 7 families, show
to have the variant.
One family with the R53C varian
WES, genotyping by LOD= 5.07 (P= 6,7 10-7)
Yu et al. Age-related 9 families (42
bead-array, Sanger One family with D90G variant:
[38] macular DNA samples)
sequencing LOD score= 1.22 (P = 0,009)
degeneration
(AMD)

Weeke et In 5 families, 7-15 very rare

al.[92] variants in 28 different genes wer
WES, Sanger
Atrial fibrillation 6 families detected. One specific disease
sequencing
causing variant was not found in
any of the families.

An et al. Were looking for both de novo an

40 trio or
[48] inherited variants and several we
Autism spectrum sibling
identified. Most promising was th
disorder families (48 WES
in 4/48 cases, inherited variants i
(ASD) affected, 80
the L1CAM interaction pathway
controls)
were found.

Cukier et 40 families 32 rare SNPs, not previously

al.[93] (164 WES, SNP associated with ASD, segregated
Autism spectrum
individuals in genotyping, Sanger 2 families.
disorder
total, 105 sequencing, IBD
(ASD)
affected, 59 analysis
unaffected)
Shi et al. WES, SNP 7 candidate genes with rare varia
Autism spectrum 1 family (10
[91] genotyping, Sanger shared by the 2 affected individu
disorder individuals, 2
sequencing, IBD were detected. Whether they are
(ASD) affected)
analysis disease causing was not confirme
Cruceanu A rare missense variant (position
et al. [37] 116652892) on chromosome 11
WES, Sanger-
found to segregate in a family. Th
sequencing
variant was not present in
25 families
Bipolar disorder unaffected family members.
analyzed
Egawa et 1 family (2 Two variants WDR90 V1125fs an
al.[59] affected twins, EFCAB5 L1210fs, identified to b
the mother and transmitted from the father to a
2 brothers monozygotic twin pair. Variants
WES, Sanger were absent in unaffected brother
were
Bipolar disorder sequencing, They were not redetected in a
unaffected,
genotyping assay follow-up study in unrelated
father was
undiagnosed individuals.
but had
symptoms)

Georgi et 388 A number of candidate-genes fou

al. [46] individuals to be shared by 3 linked families.
from a large single causal gene or variant was
(Old Order not found.
Amish)
GWAS, WGS,
Bipolar disorder pedigree with
Linkage-analysis
many nuclear
families. WGS
of 50
individuals (23
affected)
84 segregating rare variants were
found in 82 genes.
Goes et al.
Follow up in 3 case-control
[44]
samples (a total of 3,541 cases an
4,774 controls) resulted in detect
8 families (6.9 of 3 variants with significant
affected on association and OR >1. Genes an
Bipolar disorder average, 55 WES the OR for the 3 variants are liste
individuals in below.
total) MLK4 with OR = 2.73 (P = 0.016
APPL2 with OR = 6.7 (P = 0.039
HSP90AA1 with OR = 2.78 (P =
0.045)

Matoba et Bipolar disorder 50 trio families WES Preliminary analysis showed

al. approximately 43 variants on
(ongoing) average to be transmitted to the
[47] proband (the child) in 7 families.

Strauss et The rs78247304 variant in the

al. [53] 4 pedigrees KCNH7 gene was found by WES
with a total of and filtering of DNA from 7
WES, genotyping by
Bipolar disorder 26 family individuals with bipolar disorder
SNP array
members (14 from 4 different families. The
affected) finding was not genome wide
significant.
7 rare variants were found to
segregate with affection status in
Tanaka et
the pedigree. One of them, N107
al.[63]
in EEA1, was found to be
significantly more frequent in 67
1 family (16 lean diabetes subjects than in 105
Linkage-analysis,
living normoglycemic controls
Diabetes (Type II) WES, SNP
individuals, 13 (P = 0.022, Fishers exact test).
genotyping
affected)
p.N1072K was further detected in
3/64 unrelated familial diabetes
cases (MAF = 2.3%).
A nonsense variant in APPL1 fou
to segregate in an Italian family
Prudente et
(counting 28 individuals, 10 of
al. [55]
them affected,10 unaffected
carriers).
WES, Sanger
Diabetes (Type II) 60 families
sequencing
A missense variant in APPL1 fou
to segregate in an American fami
(counting 12 individuals, 5 of the
affected, 1 unaffected carrier).

Okou et al. A missense variant,

[64] c.694A>C in FOXP3 on
1 family (5 SNP-genotyping,
Inflammatory chromosome X identified t
individuals, WES, Sanger
bowel disease be inherited from an
4 affected) sequencing
affected mother to her 3
affected sons.
 A total of 68 rare exonic variants
Farlow et 68 genes were identified in the 7
al.[94] families. 8 of them segregated wi
all aneurysmal phenotypes and
were not carried by unaffected
individuals. The variants were
Intracranial Linkage-analysis,
7 families found in following genes: KLF11
aneurysm WES,
ABCC3, TANC2, ALMS1,
ARHGEF1, SMEK2, HTRA2, and
NDST1.

A rare variant in PLD3 gene

(rs145999145) segregating in 2
Cruchaga
pedigrees.
et al. [36]
The variant was associated with
14 families LOAD risk.
Late onset (WES on 29 OR = 2.10 in 4,998 sporadic case
alzheimers disease affected and 11 WES, genotyping vs. 6,356 controls (95% CI = [1.4
(LOAD) unaffected 2,99] P = 2.39 10-10-)
individuals) OR = 3.39 (95% CI = [2.14; 5.39
P = 1.18 10-6) in 1,106
familial cases vs. 6,356 controls n
related to the cases.
A rare variant in the TTC3 gene
(rs377155188) segregated perfec
Kohli et al.
with LOAD in the pedigree. 1
[43]
unaffected carrier of 5 tested.
1 family with
Further study in a case-control
15 affected WES, linkage
Late onset dataset (6,669 cases, 5,585
(DNA samples analysis, genotyping
alzheimers disease controls) resulted in OR 3.35 (did
from 11 by bead array,
(LOAD) not reach statistical significance.
affected and 5 Sanger sequencing
not specified).
unaffected)

Saad et al. Late onset 77 individuals GWAS, linkage- Several candidate genes detected
[95] alzheimers disease from families analysis, WES, IBD Found one SNP (rs2291516, MA
(LOAD; age at with multiple analysis = 0.08, P value = 4.12 107) wi
onset) affected Bonferroni-corrected significance
(inclusion of (0.05/39 993 = 1.25 106) in the
up to 4 gene RGL3. Further 14 SNPs wit
affected per. higher P-values were found in 11
family) different genes.
 A rare variant
(rs137875858) in UNC5C gene
Wetzel- segregating in a pedigree. The
Smith et al. variant was present in all cases w
1 pedigree
[42] available DNA (6) and 2
with 8 affected
(further unaffected. Further analysis on 8
analysis on Parametric linkage other probands resulted in 4 othe
Late onset
863 probands analysis, WGS, cases positive for the variant of
alzheimers disease
from other WES, genotyping which one showed to segregate
(LOAD)
families and assays with cases in the family.
linkage-
analysis in 4 of
OR = 2.15 in unrelated 8,050 cas
these families)
vs. 98,194 controls (95% CI =
[1.21;3.84], P = 0.0095)

Identification of variants in 4 gen

Aylward et present in 3 families. Variants in
al.[60] of the genes, ACSS2 and PHYH,
Nonsyndromic segregated with NSCLP as a
WES, Sanger
cleft lip and palate 25 families dominant variant with incomplete
sequencing
(NSCLP) penetrance.

The mutation c.574C>T in CD16

was found in all affected
Nyegaard GWAS, linkage-
individuals.
et al. [45] One family (29 analysis, NGS only
Nonsyndromic living at the locus side by
hearing impairment individuals, 15 using a custom LOD-score of the locus 5.1.
affected) designed sequencing
array.
A pedigree A duplication in the A2ML1 gene
consisting 134 (c.2478_2485dupGGCTAAAT
Santos- Otitis media WES, Sanger
individuals (p.Ser829Trpfs*9) possibly
cortez et al. sequencing.
(from an segregated with the disease in the
[57]
intermarried, pedigree.
indigenous
Filipino
LOD-score 7.5.
community).

(DNA from
51)
Deng et al. A rare missense variant in
1 family with
[58] TMEM230 were present in the
81 members, Likage analysis,
DNA from the 13 affected
Parkinsons disease 15 affected WES, Sanger
individuals tested. It is unclear
(DNA samples sequencing
whether they found unaffected
from 65)
carriers.

Johnson et
al.[61] 2 families (18
A rare SNP (rs111033530) residin
individuals in
within the GPR98 gene was
Preeclampsia total, 7 WES
detected in 1 family.
affected, 11
controls)

Liu et al. Primary open angle 1 family (16 Several mutations in CD2, PKHD
WES
[96] glaucoma affected) PAH and FUT7 were identified.

Okada et A rare non-synonymous mutation

al.[62] PLB1 (p.G755R) were found to c
1 pedigree (49
segregate with RA, showing a
Rheumatoid individuals, 8 GWAS, IBD
dominant inheritance with
arthritis (RA) affected, 10 mapping, WES
incomplete penetrance. It was
deceased)
present in all 5 tested cases and in
of 16 unaffected (P = 0.009).
25 rare SNPs and a deletion
detected, each unique, to one of t
Homann et
9 families, and present in all the
al. [97]
sequenced affected members in th
family. Some of them also presen
Schizophrenia in controls.
9 families (90 WES
(SCZ) Several of the genes involved hav
DNA samples)
previously been found to have
association with neurodevelopme
and schizophrenia.

Thygesen Formal thought 6 pedigrees = a Genotyping of SNPs A haplotype on chromosome 6

et al. [49] disorder/schizophre total of 618 and microsattelites found to segregate with thought
nia (SCZ) individuals. by bead-array, disturbances in 31 individuals in
 pedigree with max-LOD score of
linkage-analysis, WGS on three of these individua
(DNA samples
WGS, Sanger detected a single nucleotide
from 256)
sequencing deletion (chr6: 1643777205
AG>A).

Timms et 5 families 4 different variants found to

al. [54] (DNA WES, Sanger segregate in 4 families in 3 genes
Schizophrenia
available for sequencing, GWAS associated with the NMDA-
(SCZ)
24 affected and for linkage analysis receptor.
17 unaffected)

Van Den One CNV found in 6 family

Bossche et members in a family, of which 4
al. [41] had schizophrenia related disorde
Bead chip CNV
2 CNVs found in another family.
Schizophrenia analysis, multiplex
8 families One of them in the mother who h
(SCZ) amplicon
symptoms but no disorder, and 2
quantification
affected children. The other was
found in the healthy father and al
three affected children.
A rare missense variation c.9575
>G (p.Thr3192Ser) in RELN,
Zhou et al.
which is known as a risk gene for
[65]
1 family (12 Linkage-analysis, SCZ, was indentified in affected
Schizophrenia individuals and absent in
individuals, 6 WES, Sanger
(SCZ) unaffected. It was not detected in
affected) sequencing
the 500 unaffected control
individuals.